Quinolone antibacterial agents

ABSTRACT

Compounds of formula I and methods for their preparation are disclosed. Further disclosed are methods of making biologically active compounds of formula I as well as pharmaceutically acceptable compositions comprising compounds of formula I. Compounds of formula I as disclosed herein can be used in a variety of applications including use as antibacterial agents.

FIELD OF THE INVENTION

The invention relates to compounds which exhibit antibacterial activity,methods for their preparation, as well as pharmaceutically acceptablecompositions comprising such compounds.

BACKGROUND OF THE INVENTION

Antibacterial resistance is a global clinical and public health problemthat has emerged with alarming rapidity in recent years. Resistance is aproblem in the community as well as in health care settings, wheretransmission of bacteria is greatly amplified. Because multiple drugresistance is a growing problem, physicians are now confronted withinfections for which there is no effective therapy. The morbidity,mortality, and financial costs of such infections pose an increasingburden for health care systems worldwide. As a result, alternative andimproved agents are needed for the treatment of bacterial infections,particularly for the treatment of infections caused by resistant strainsof bacteria.

SUMMARY OF THE INVENTION

These and other needs are met by the present invention, which isdirected to a compound of formula I:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X is N or C, provided that when X is N, R₅ is absent;    -   R₁ is (C₁-C₆)alkyl,        -   halo(C₁-C₆)alkyl,        -   (C₃-C₆)cycloalkyl,        -   halo(C₃-C₆)cycloalkyl        -   aryl, and        -   heteroaryl;    -   R₂ is H,        -   NH₂,        -   NH(C₁-C₆)alkyl,        -   NH(C₃-C₆)cycloalkyl,        -   NH-heteroaryl,        -   NHSO₂—(C₁-C₆)alkyl,        -   NHSO₂-aryl,        -   NHSO₂-heteroaryl,        -    wherein, Q is O or is absent, and R_(2a) and R_(2a) are            each independently H or (C₁-C₆)alkyl, or taken together with            the carbons to which they are attached form a 3, 4, 5, or            6-membered substituted or unsubstituted ring, and R_(2b) is            (C₁-C₆)alkyl, aryl, or heteroaryl,        -    wherein R_(2a) and R_(2a′) are as defined above,        -    wherein        -    indicates the point of attachment, p is 0 or 1, and            -   R_(2c) is H,                -   (C₁-C₆)alkyl,                -   (C₃-C₇)cycloalkyl,                -   aryl,                -   heterocyclo,                -   heteroaryl, or                -    wherein R_(2a), R_(2b), and Q are as defined above,                    n is an integer from 0 to 10, and Y is OH, OPO(OH)₂,                    OPO(O(C₁-C₆)alkyl)₂, or NR_(2d)R_(2e), wherein                    R_(2d) and R_(2e) are each independently H,                    (C₁-C₆)alkyl, or (C₃-C₇)cycloalkyl,        -    wherein q is 0 or 1, R_(2f) and R_(2f′) are each            independently H, (C₁-C₆)alkyl, aryl, or heteroaryl, or taken            together with the carbon to which they are attached form a            3, 4, 5, or 6 membered ring, and R_(2g) is            -   (C₁-C₆)alkyl,            -   (C₃-C₇)cycloalkyl,            -   aryl, or            -   heterocyclo, or            -   heteroaryl;    -   R₃, R₄, and R₅ are each independently H,        -   halo,        -   NH₂,        -   (C₁-C₆)alkyl,        -   halo(C₁-C₆)alkyl,        -   (C₁-C₆)alkoxy, or        -   halo(C₁-C₆)alkoxy;    -   R_(c), R_(d), R_(e), R_(f), and R_(g) are each independently H,        -   halo,        -   (C₁-C₆)alkyl,        -   OH,        -   OPO(OH)₂,        -   OPO(O(C₁-C₆)alkyl)₂,        -    wherein        -    indicates the point of attachment and Q is O or is absent,        -   R_(ii)O(C₁-C₆)alkyl,        -   R_(ii)O(C₁-C₆)haloalkyl,        -   R_(ii)O(C₃-C₆)cycloalkyl,        -   R_(ii)O(C₁-C₆)alkyl-O—,        -   R_(ii)O(C₁-C₆)haloalkyl-O—,        -   R_(ii)O(C₃-C₆)cycloalkyl-O—,        -    wherein        -    indicates the point of attachment, het is a 5- or            6-membered heterocyclo or heteroaryl group that does not            contain an NH, and x is an integer of from 0 to 10;        -    wherein        -    indicates the point of attachment, het is as defined above,            and y is an integer of from 1 to 10,            -   wherein R_(ii) is H,                -   (C₁-C₆)alkyl,                -   PO(OH)₂, or                -    as defined above;            -   provided that 3 or fewer of R_(c) R_(d), R_(e), and                R_(f) are H; or        -   R_(c) and R_(e), together with the carbons to which they are            attached, form a substituted or unsubstituted 4, 5, or            6-membered ring containing 0, 1, 2, or 3 heteroatoms            selected from NH N(C₁-C₆)alkyl, S, or O; or        -   R_(c) and R_(d), or R_(e) and R_(f), independently, together            with the carbon to which they are attached, form a            substituted or unsubstituted 3, 4, 5, or 6-membered ring            containing 0, 1, 2, or 3 heteroatoms selected from NH,            N(C₁-C₆)alkyl, S, or O.

What is also provided is a compound of formula II:

-   -   or a pharmaceutically acceptable salt thereof, wherein    -   X is N or C, provided that when X is N, R₅ is absent;    -   R₁ is (C₁-C₆)alkyl,        -   halo(C₁-C₆)alkyl,        -   (C₃-C₆)cycloalkyl,        -   halo(C₃-C₆)cycloalkyl        -   aryl, and        -   heteroaryl;    -   R₂ is H,        -   NH₂,        -   NH(C₁-C₆)alkyl,        -   NH(C₃-C₆)cycloalkyl,        -   NH-heteroaryl,        -   NHSO₂—(C₁-C₆)alkyl,        -   NHSO₂-aryl,        -   NHSO₂-heteroaryl,        -    wherein, Q is O or is absent, and R_(2a) and R_(2a′) are            each independently H or (C₁-C₆)alkyl, or taken together with            the carbons to which they are attached form a 3, 4, 5, or            6-membered substituted or unsubstituted ring, and R_(2b) is            (C₁-C₆)alkyl, aryl, or heteroaryl,        -    wherein R_(2a) and R_(2a′) are as defined above,        -    wherein        -    indicates the point of attachment, p is 0 or 1, and            -   R₂C is H, —                -   (C₁-C₆)alkyl,                -   (C₃-C₇)cycloalkyl,                -   aryl,                -   heterocyclo,                -   heteroaryl, or                -    wherein R_(2a), R_(2b), and Q are as defined above,                    n is an integer from 0 to 10, and Y is OH,                    OP(O)(OH)₂, OPO(O(C₁-C₆)alkyl)₂, or NR_(2d)R_(2e),                    wherein R_(2d) and R_(2e) are each independently H,                    (C₁-C₆)alkyl, or (C₃-C₇)cycloalkyl,        -    wherein q is 0 or 1, R_(2f) and R_(2f′) are each            independently H, (C₁-C₆)alkyl, aryl, or heteroaryl, or taken            together with the carbon to which they are attached form a            3, 4, 5, or 6 membered ring, and R_(2g) is            -   (C₁-C₆)alkyl,            -   (C₃-C₇)cycloalkyl,            -   aryl, or            -   heterocyclo, or            -   heteroaryl;    -   R₃, R₄, and R₅ are each independently H,        -   halo,        -   NH₂,        -   (C₁-C₆)alkyl,        -   halo(C₁-C₆)alkyl,        -   (C₁-C₆)alkoxy, or        -   halo(C₁-C₆)alkoxy; and    -   R_(c) is OPO(OH)₂,        -   OPO(O(C₁-C₆)alkyl)₂,        -    wherein        -    indicates the point of attachment and Q is O or is absent,        -   R_(ii)O(C₂-C₆)alkyl,        -   R_(ii)O(C₁-C₆)haloalkyl,        -   R_(ii)O(C₃-C₆)cycloalkyl,        -   R_(ii)O(C₁-C₆)alkyl-O—,        -   R_(ii)O(C₁-C₆)haloalkyl-O—,        -   R_(ii)O(C₃-C₆)cycloalkyl-O—,        -    wherein        -    indicates the point of attachment, het is a 5- or            6-membered heterocyclo or heteroaryl group that does not            contain an NH, and x is an integer of from 0 to 10;        -    wherein        -    indicates the point of attachment, het is as defined above,            and y is an integer of from 1 to 10,            -   wherein R_(ii) is H,                -   (C₁-C₆)alkyl,                -   PO(OH)₂,                -   PO(O(C₁-C₆)alkyl)₂, or                -    as defined above.

What is also provided is a compound which is:

-   3-Amino-1-cyclopropyl-6-fluoro-7-(3-hydroxymethyl-pyrrolidin-1-yl)-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-7-[3-(hydroxy-oxazol-4-yl-methyl)-pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-7-[3-(2,2-difluoro-1-hydroxy-ethyl)-pyrrolidin-1-yl]-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-7-[3-(furan-2-yl-hydroxy-methyl)-pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-7-[3-(1,2-dihydroxy-1-methyl-ethyl)-pyrrolidin-1-yl]-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-7-[3-(hydroxy-oxazol-2-yl-methyl)-pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-7-[3-(hydroxy-oxazol-2-yl-methyl)-pyrrolidin-1-yl]-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-7-[3-(2,2-difluoro-1-hydroxy-propyl)-pyrrolidin-1-yl]-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-7-[3-(2-hydroxy-ethyl)-pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-7-{3-[hydroxy-(1-hydroxymethyl-cyclopropyl)methyl]-pyrrolidin-1-yl}-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-7-[3-(1,2-dihydroxy-ethyl)-pyrrolidin-1-yl]-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-[3-(2,2,2-trifluoro-1-hydroxyethyl)-pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;    or-   3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methoxymethyl-pyrrolidin-1-yl)-1H-quinazoline-2,4-dione.

What is also provided is a compound of formula III

-   -   or a pharmaceutically acceptable salt thereof, wherein    -   X is N or C, provided that when X is N, R₅ is absent;    -   R₁ is (C₁-C₆)alkyl,        -   halo(C₁-C₆)alkyl,        -   (C₃-C₆)cycloalkyl,        -   halo(C₃-C₆)cycloalkyl        -   aryl, and        -   heteroaryl;    -   R₂ is H,        -   NH₂,        -   NH(C₁-C₆)alkyl,        -   NH(C₃-C₆)cycloalkyl,        -   NH-heteroaryl,        -   NHSO₂—(C₁-C₆)alkyl,        -   NHSO₂-aryl,        -   NHSO₂-heteroaryl,        -    wherein, Q is O or is absent, and R_(2a) and R_(2a′) are            each independently H or (C₁-C₆)alkyl, or taken together with            the carbons to which they are attached form a 3, 4, 5, or            6-membered substituted or unsubstituted ring, and R_(2b) is            (C₁-C₆)alkyl, aryl, or heteroaryl,        -    wherein R_(2a) and R_(2a′) are as defined above,        -    wherein        -    indicates the point of attachment, p is 0 or 1, and            -   R_(2c) is H,                -   (C₁-C₆)alkyl,                -   (C₃-C₇)cycloalkyl,                -   aryl,                -   heterocyclo,                -   heteroaryl, or                -    wherein R_(2a), R_(2b), and Q are as defined above,                    n is an integer from 0 to 10, and Y is OH,                    OPO(O(C₁-C₆)alkyl)₂, OPO(OH)₂, or NR_(2d)R_(2e),                    wherein R_(2d) and R_(2e) are each independently H,                    (C₁-C₆)alkyl, or (C₃-C₇)cycloalkyl,        -    wherein q is 0 or 1, R_(2f) and R_(2f′) are each            independently H, (C₁-C₆)alkyl, aryl, or heteroaryl, or taken            together with the carbon to which they are attached form a            3, 4, 5, or 6 membered ring, and R_(2g) is            -   (C₁-C₆)alkyl,            -   (C₃-C₇)cycloalkyl,            -   aryl, or            -   heterocyclo, or            -   heteroaryl;    -   R₃, R₄, and R₅ are each independently H,        -   halo,        -   NH₂,        -   (C₁-C₆)alkyl,        -   halo(C₁-C₆)alkyl,        -   (C₁-C₆)alkoxy, or        -   halo(C₁-C₆)alkoxy; and    -   R_(c) is OH,        -   OPO(OH)₂,        -   OPO(O(C₁-C₆)alkyl)₂,        -    wherein        -    indicates the point of attachment and Q is O or is absent,        -   R_(ii)O(C₁-C₆)alkyl,        -   R_(ii)O(C₁-C₆)haloalkyl,        -   R_(ii)O(C₃-C₆)cycloalkyl,        -   R_(ii)O(C₁-C₆)alkyl-O—,        -   R_(ii)O(C₁-C₆)haloalkyl-O—,        -   R_(ii)O(C₃-C₆)cycloalkyl-O—,        -    wherein        -    indicates the point of attachment, het is a 5- or            6-membered heterocyclo or heteroaryl group that does not            contain an NH, and x is an integer of from 0 to 10;        -    wherein        -    indicates the point of attachment, het is as defined above,            and y is an integer of from 1 to 10; wherein R_(ii) is H,            -   (C₁-C₆)alkyl,            -   PO(OH)₂,            -   PO(O(C₁-C₆)alkyl)₂, or            -    as defined above; and    -   R_(d) is halo,        -   (C₁-C₆)alkyl,        -   R_(ii)O(C₁-C₆)alkyl,        -   R_(ii)O(C₁-C₆)haloalkyl,        -   R_(ii)O(C₃-C₆)cycloalkyl,        -   R_(ii)O(C₁-C₆)alkyl-O—,        -   R_(ii)O(C₁-C₆)haloalkyl-O—,        -   R_(ii)O(C₃-C₆)cycloalkyl-O—, or        -    wherein        -    indicates the point of attachment and Q is O or is absent.

What is also provided is a compound of formula IV

-   -   or a pharmaceutically acceptable salt thereof, wherein    -   X is N or C, provided that when X is N, R₅ is absent;    -   R₁ is (C₁-C₆)alkyl,        -   halo(C₁-C₆)alkyl,        -   (C₃-C₆)cycloalkyl,        -   halo(C₃-C₆)cycloalkyl        -   aryl, and        -   heteroaryl;    -   R₂ is H,        -   NH₂,        -   NH(C₁-C₆)alkyl,        -   NH(C₃-C₆)cycloalkyl,        -   NH-heteroaryl,        -   NHSO₂—(C₁-C₆)alkyl,        -   NHSO₂-aryl,        -   NHSO₂-heteroaryl,        -    wherein, Q is O or is absent, and R_(2a) and R_(2a′) are            each independently H or (C₁-C₆)alkyl, or taken together with            the carbons to which they are attached form a 3, 4, 5, or            6-membered substituted or unsubstituted ring, and R_(2b) is            (C₁-C₆)alkyl, aryl, or heteroaryl,        -    wherein R_(2a) and R_(2a′) are as defined above,        -    wherein        -    indicates the point of attachment, p is 0 or 1, and            -   R_(2c) is H,                -   (C₁-C₆)alkyl,                -   (C₃-C₇)cycloalkyl,                -   aryl,                -   heterocyclo,                -   heteroaryl, or                -    wherein R_(2a), R_(2b), and Q are as defined above,                    n is an integer from 0 to 10, and Y is OH,                    OP(O)(O(C₁-C₆)alkyl)₂, OP(O)(OH)₂, or NR_(2d)R_(2e),                    wherein R_(2d) and R_(2e) are each independently H,                    (C₁-C₆)alkyl, or (C₃-C₇)cycloalkyl,        -    wherein q is 0 or 1, R_(2f) and R_(2f′) are each            independently H, (C₁-C₆)alkyl, aryl, or heteroaryl, or taken            together with the carbon to which they are attached form a            3, 4, 5, or 6 membered ring, and R_(2g) is            -   (C₁-C₆)alkyl,            -   (C₃-C₇)cycloalkyl,            -   aryl, or            -   heterocyclo, or            -   heteroaryl;    -   R₃, R₄, and R₅ are each independently H,        -   halo,        -   NH₂,        -   (C₁-C₆)alkyl,        -   halo(C₁-C₆)alkyl,        -   (C₁-C₆)alkoxy, or        -   halo(C₁-C₆)alkoxy; and    -   R_(c) is OH,        -   OPO(OH)₂,        -   OPO(O(C₁-C₆)alkyl)₂,        -    wherein        -    indicates the point of attachment and Q is O or is absent,        -   R_(ii)O(C₁-C₆)alkyl,        -   R_(ii)O(C₁-C₆)haloalkyl,        -   R_(ii)O(C₃-C₆)cycloalkyl,        -   R_(ii)O(C₁-C₆)alkyl-O—,        -   R_(ii)O(C₁-C₆)haloalkyl-O—,        -   R_(ii)O(C₃-C₆)cycloalkyl-O—,        -    wherein        -    indicates the point of attachment, het is a 5- or            6-membered heterocyclo or heteroaryl group that does not            contain an NH, and x is an integer of from 0 to 10;        -    wherein        -    indicates the point of attachment, het is as defined above,            and y is an integer of from 1 to 10;        -   wherein R_(ii) is H,            -   (C₁-C₆)alkyl,            -   PO(OH)₂,            -   PO(O(C₁-C₆)alkyl)₂,            -    as defined above; and    -   R_(e) is halo    -    wherein    -    indicates the point of attachment and Q is O or is absent,        -   R_(ii)O(C₁-C₆)alkyl,        -   R_(ii)O(C₁-C₆)haloalkyl,        -   R_(ii)O(C₃-C₆)cycloalkyl,        -   R_(ii)O(C₁-C₆)alkyl-O—,        -   R_(ii)O(C₁-C₆)haloalkyl-O—,        -   R_(ii)O(C₃-C₆)cycloalkyl-O—,        -    wherein        -    indicates the point of attachment, het is a 5- or            6-membered heterocyclo or heteroaryl group that does not            contain an NH, and x is an integer of from 0 to 10;        -    wherein        -    indicates the point of attachment, het is as defined above,            and y is an integer of from 1 to 10;        -   wherein R_(ii) is H,            -   (C₁-C₆)alkyl,            -   PO(OH)₂,            -   PO(O(C₁-C₆)alkyl)₂, or            -    as defined above.

What is also provided is a compound which is

-   3-Amino-7-(3,4-meso    bis-hydroxymethyl-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;-   3-Amino-7-(3,4-tratis    bis-hydroxymethyl-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;-   3-Amino-1-cyclopropyl-7-(3,4-meso    dihydroxy-pyrrolidin-1-yl)-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[3,4-bis-meso    (2-hydroxy-ethyl)-pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;    or-   3-Amino-1-cyclopropyl-6-fluoro-7-(3-fluoro-4-hydroxymethyl-pyrrolidin-1-yl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione.

What is also provided is a compound of formula V

-   -   or a pharmaceutically acceptable salt thereof, wherein    -   X is N or C, provided that when X is N, R₅ is absent;    -   R₁ is (C₁-C₆)alkyl,        -   halo(C₁-C₆)alkyl,        -   (C₃-C₆)cycloalkyl,        -   halo(C₃-C₆)cycloalkyl        -   aryl, and        -   heteroaryl;    -   R₂ is H,        -   NH₂,        -   NH(C₁-C₆)alkyl,        -   NH(C₃-C₆)cycloalkyl,        -   NH-heteroaryl,        -   NHSO₂—(C₁-C₆)alkyl,        -   NHSO₂-aryl,        -   NHSO₂-heteroaryl,        -    wherein, Q is O or is absent, and R_(2a) and R_(2a′) are            each independently H or (C₁-C₆)alkyl, or taken together with            the carbons to which they are attached form a 3, 4, 5, or            6-membered substituted or unsubstituted ring, and R_(2b) is            (C₁-C₆)alkyl, aryl, or heteroaryl,        -    wherein R_(2a) and R_(2a′) are as defined above,        -    wherein        -    indicates the point of attachment, p is 0 or 1, and            -   R_(2c) is H,                -   (C₁-C₆)alkyl,                -   (C₃-C₇)cycloalkyl,                -   aryl,                -   heterocyclo,                -   heteroaryl, or                -    wherein R_(2a), R_(2b), and Q are as defined above,                    n is an integer from 0 to 10, and Y is OH,                    OP(O)(O(C₁-C₆)alkyl)₂, OP(O)(OH)₂, or NR_(2d)R_(2e),                    wherein R_(2d) and R_(2e) are each independently H,                    (C₁-C₆)alkyl, or (C₃-C₇)cycloalkyl,        -    wherein q is 0 or 1, R_(2f) and R_(2f′) are each            independently H, (C₁-C₆)alkyl, aryl, or heteroaryl, or taken            together with the carbon to which they are attached form a            3, 4, 5, or 6 membered ring, and R_(2g) is            -   (C₁-C₆)alkyl,            -   (C₃-C₇)cycloalkyl,            -   aryl, or            -   heterocyclo, or            -   heteroaryl;    -   R₃, R₄, and R₅ are each independently H,        -   halo,        -   NH₂,        -   (C₁-C₆)alkyl,        -   halo(C₁-C₆)alkyl,        -   (C₁-C₆)alkoxy, or        -   halo(C₁-C₆)alkoxy; and    -   R_(c) is OH,        -   OPO(OH)₂,        -   OPO(O(C₁-C₆)alkyl)₂,        -    wherein        -    indicates the point of attachment and Q is O or is absent,        -   R_(ii)O(C₁-C₆)alkyl,        -   R_(ii)O(C₁-C₆)haloalkyl,        -   R_(ii)O(C₃-C₆)cycloalkyl,        -   R_(ii)O(C₁-C₆)alkyl-O—,        -   R_(ii)O(C₁-C₆)haloalkyl-O—,        -   R_(ii)O(C₃-C₆)cycloalkyl-O—,        -    wherein        -    indicates the point of attachment, het is a 5- or            6-membered heterocyclo or heteroaryl group that does not            contain an NH, and x is an integer of from 0 to 10;        -    wherein        -    indicates the point of attachment, het is as defined above,            and y is an integer of from 1 to 10; wherein R_(ii) is H,            -   (C₁-C₆)alkyl,            -   PO(OH)₂,            -   PO(O(C₁-C₆)alkyl)₂,            -    as defined above; and    -   R_(e) and R_(f) are each independently halo,        -   wherein        -   indicates the point of attachment and Q is O or is absent,        -   R_(ii)O(C₁-C₆)alkyl,        -   R_(ii)O(C₁-C₆)haloalkyl,        -   R_(ii)O(C₃-C₆)cycloalkyl,        -   R_(ii)O(C₁-C₆)alkyl-O—,        -   R_(ii)O(C₁-C₆)haloalkyl-O—,        -   R_(ii)O(C₃-C₆)cycloalkyl-O—,        -    wherein        -    indicates the point of attachment, het is a 5- or            6-membered heterocyclo or heteroaryl group that does not            contain an NH, and x is an integer of from 0 to 10;        -    wherein        -    indicates the point of attachment, het is as defined above,            and y is an integer of from 1 to 10;        -   wherein R_(ii) is H,            -   (C₁-C₆)alkyl,            -   PO(OH)₂,            -   PO(O(C₁-C₆)alkyl)₂, or        -    as defined above; or    -   R_(e) and R_(f) taken together with the carbons to which the are        attached form an optionally substituted 3, 4, 5, 6 membered        ring.

What is also provided is a compound which is:

-   3-Amino-1-cyclopropyl-6-fluoro-7-(7-hydroxymethyl-5-aza-spiro[2.4]hept-5-yl)-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-7-(7-hydroxymethyl-5-aza-spiro[2.4]hept-5-yl)-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-7-(7-hydroxymethyl-5-aza-spiro[2.4]hept-5-yl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione;-   3-Amino-1-cyclopropyl-7-[7-(1,2-dihydroxy-ethyl)-5-aza-spiro[2.4]hept-5-yl]-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-7-[7-(1,2-dihydroxy-ethyl)-5-aza-spiro[2.4]hept-5-yl]-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-7-[7-(1,2-dihydroxy-ethyl)-5-aza-spiro[2.4]hept-5-yl]-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-7-(4-hydroxymethyl-3,3-dimethyl-pyrrolidin-1-yl)-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-7-(4-hydroxymethyl-3,3-dimethyl-pyrrolidin-1-yl)-8-methyl-1H-quinazoline-2,4-dione;    or-   3-Amino-1-cyclopropyl-6-fluoro-7-(4-hydroxymethyl-3,3-dimethyl-pyrrolidin-1-yl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione.

What is also provided is a compound of formula VI

-   -   or a pharmaceutically acceptable salt thereof, wherein    -   X is N or C, provided that when X is N, R₅ is absent;    -   R₁ is (C₁-C₆)alkyl,        -   halo(C₁-C₆)alkyl,        -   (C₃-C₆)cycloalkyl,        -   halo(C₃-C₆)cycloalkyl        -   aryl, and        -   heteroaryl;    -   R₂ is H,        -   NH₂,        -   NH(C₁-C₆)alkyl,        -   NH(C₃-C₆)cycloalkyl,        -   NH-heteroaryl,        -   NHSO₂—(C₁-C₆)alkyl,        -   NHSO₂-aryl,        -   NHSO₂-heteroaryl,        -    wherein, Q is O or is absent, and R_(2a) and R_(2a′) are            each independently H or (C₁-C₆)alkyl, or taken together with            the carbons to which they are attached form a 3, 4, 5, or            6-membered substituted or unsubstituted ring, and R_(2b) is            (C₁-C₆)alkyl, aryl, or heteroaryl,        -    wherein R_(2a) and R_(2a′) are as defined above,        -    wherein        -    indicates the point of attachment, p is 0 or 1, and            -   R₂C is H,                -   (C₁-C₆)alkyl,                -   (C₃-C₇)cycloalkyl,                -   aryl,                -   heterocyclo,                -   heteroaryl, or                -    wherein R_(2a), R_(2b), and Q are as defined above,                    n is an integer from 0 to 10, and Y is OH,                    OP(O)(O(C₁-C₆)alkyl)₂, OP(O)(OH)₂, or NR_(2d)R_(2e),                    wherein R_(2d) and R_(2e) are each independently H,                    (C₁-C₆)alkyl, or (C₃-C₇)cycloalkyl,        -    wherein q is 0 or 1, R_(2f) and R_(2f′) are each            independently H, (C₁-C₆)alkyl, aryl, or heteroaryl, or taken            together with the carbon to which they are attached form a            3, 4, 5, or 6 membered ring, and R_(2g) is            -   (C₁-C₆)alkyl,            -   (C₃-C₇)cycloalkyl,            -   aryl, or            -   heterocyclo, or            -   heteroaryl;    -   R₃, R₄, and R₅ are each independently H,        -   halo,        -   NH₂,        -   (C₁-C₆)alkyl,        -   halo(C₁-C₆)alkyl,        -   (C₁-C₆)alkoxy, or        -   halo(C₁-C₆)alkoxy; and    -   R_(c) is OH,        -   OPO(OH)₂,        -   OPO(O(C₁-C₆)alkyl)₂,        -    wherein        -    indicates the point of attachment and Q is O or is absent,        -   R_(ii)O(C₁-C₆)alkyl,        -   R_(ii)O(C₁-C₆)haloalkyl,        -   R_(ii)O(C₃-C₆)cycloalkyl,        -   R_(ii)O(C₁-C₆)alkyl-O—,        -   R_(ii)O(C₁-C₆)haloalkyl-O—,        -   R_(ii)O(C₃-C₆)cycloalkyl-O—,        -    wherein        -    indicates the point of attachment, het is a 5- or            6-membered heterocyclo or heteroaryl group that does not            contain an NH, and x is an integer of from 0 to 10;        -    wherein        -    indicates the point of attachment, het is as defined above,            and y is an integer of from 1 to 10;        -   wherein R_(ii) is H,            -   (C₁-C₆)alkyl,            -   PO(OH)₂,            -   PO(O(C₁-C₆)alkyl)₂,            -    as defined above; and    -   R_(e) is halo        -   wherein        -    indicates the point of attachment and Q is O or is absent,        -   R_(ii)O(C₁-C₆)alkyl,        -   R_(ii)O(C₁-C₆)haloalkyl,        -   R_(ii)O(C₃-C₆)cycloalkyl,        -   R_(ii)O(C₁-C₆)alkyl-O—,        -   R_(ii)O(C₁-C₆)haloalkyl-O—,        -   R_(ii)O(C₃-C₆)cycloalkyl-O—,        -    wherein        -    indicates the point of attachment, het is a 5- or            6-membered heterocyclo or heteroaryl group that does not            contain an NH, and x is an integer of from 0 to 10;        -    wherein        -    indicates the point of attachment, het is as defined above,            and y is an integer of from 1 to 10;        -   wherein R_(ii) is H,            -   (C₁-C₆)alkyl,            -   PO(OH)₂,            -   PO(O(C₁-C₆)alkyl)₂, or            -    as defined above; and    -   R_(d) and R_(f) are each independently (C₁-C₆)alkyl.

What is also provided is a compound which is

-   3-Amino-7-(3,4-bis-hydroxymethyl-3,4-dimethyl-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;    or-   3-Amino-7-(3,4-bis-hydroxymethyl-3,4-dimethyl-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione.

What is also provided is a compound of formula VII

-   -   or a pharmaceutically acceptable salt thereof, wherein    -   X is N or C, provided that when X is N, R₅ is absent;    -   Z is absent or is a substituted or unsubstituted carbon linker        1, 2 0r 3 atoms in length;    -   R₁ is (C₁-C₆)alkyl,        -   halo(C₁-C₆)alkyl,        -   (C₃-C₆)cycloalkyl,        -   halo(C₃-C₆)cycloalkyl        -   aryl, and        -   heteroaryl;            -   (C₁-C₆)alkyl    -   R₃, R₄, and R₅ are each independently H,        -   halo,        -   NH₂,        -   (C₁-C₆)alkyl,        -   halo(C₁-C₆)alkyl,        -   (C₁-C₆)alkoxy, or        -   halo(C₁-C₆)alkoxy; and    -   R_(c) and R_(f) are each independently H or (C₁-C₆)alkyl;    -   R_(h) R_(i) and R_(j) are each independently H,        -   OH,        -   OPO(OH)₂,        -   OPO(O(C₁-C₆)alkyl)₂,        -    wherein        -    indicates the point of attachment and Q is O or is absent,        -   R_(ii)O(C₁-C₆)alkyl,        -   R_(ii)O(C₁-C₆)haloalkyl,        -   R_(ii)O(C₃-C₆)cycloalkyl,        -   R_(ii)O(C₁-C₆)alkyl-O—,        -   R_(ii)O(C₁-C₆)haloalkyl-O—,        -   R_(ii)O(C₃-C₆)cycloalkyl-O—,        -    wherein        -    indicates the point of attachment, het is a 5- or            6-membered heterocyclo or heteroaryl group that does not            contain an NH, and x is an integer of from 0 to 10;        -    wherein        -    indicates the point of attachment, het is as defined above,            and y is an integer of from 1 to 10;        -   wherein R_(ii) is H,            -   (C₁-C₆)alkyl,            -   PO(OH)₂,            -   PO(O(C₁-C₆)alkyl)₂,            -   as defined above; and    -   R_(i) is H or (C₁-C₆)alkyl.

What is also provided is a compound which is

-   3-Amino-1-cyclopropyl-6-fluoro-7-(4-hydroxy-4-hydroxymethyl-hexahydro-cyclopenta[c]pyrrol-2-yl)-8-methyl-1H-quinazoline-2,4-dione;    or-   3-Amino-1-cyclopropyl-6-fluoro-7-(4-hydroxy-4-hydroxymethyl-hexahydro-cyclopenta[c]pyrrol-2-yl)-8-methoxy-1H-quinazoline-2,4-dione.

What is also provided is a pharmaceutical formulation comprising acompound of one of formulas I-V admixed with a pharmaceuticallyacceptable diluent, carrier, or excipient.

What is also provided is a method of treating a bacterial infection in amammal, comprising administering to a mammal in need thereof aneffective amount of a compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to presently preferred compositionsor embodiments and methods of the invention, which constitute the bestmodes of practicing the invention presently known to the inventors.

The term “alkyl” as used herein refers to a straight or branchedhydrocarbon of from 1 to 6 carbon atoms and includes, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, n-hexyl, and the like. The alkyl group can also besubstituted with one or more of the substituents selected from lower(C₁-C₆)alkoxy, (C₁-C₆)thioalkoxy, halogen, oxo, thio, —OH, —SH, —F,—CF₃, —OCF₃, —NO₂, —CO₂H, —CO₂(C₁-C₆)alkyl, or

The term “(C₃-C₆)cycloalkyl” means a hydrocarbon ring containing from 3to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. Where possible, the cycloalkyl group may contain doublebonds, for example, 3-cyclohexen-1-yl. The cycloalkyl ring may beunsubstituted or substituted by one or more substituents selected fromalkyl, alkoxy, thioalkoxy, hydroxy, thiol, halogen, formyl, carboxyl,—CO₂(C₁-C₆)alkyl, —CO(C₁-C₆)alkyl, aryl, heteroaryl, wherein alkyl,aryl, and heteroaryl are as defined herein, or as indicated above foralkyl. Examples of substituted cycloalkyl groups includefluorocyclopropyl.

The term “halo” includes chlorine, fluorine, bromine, and iodine.

The term “aryl” means a cyclic or polycyclic aromatic ring having from 5to 12 carbon atoms, and being unsubstituted or substituted with one ormore of the substituent groups recited above for alkyl groups including,halogen, nitro, cyano —OH, —SH, —F, —CF₃, —OCF₃,

—CO₂H, —CO₂(C₁-C₆)alkyl, or —SO₂alkyl. Examples include, but are notlimited to phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-chloro-3-methylphenyl,2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl,3-chloro-2-methylphenyl, 3-chloro-4-methylphenyl,4-chloro-2-methylphenyl, 4-chloro-3-methylphenyl,5-chloro-2-methylphenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl,3,4-dichlorophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, thienyl,naphthyl, 4-thionaphthyl, tetralinyl, anthracinyl, phenanthrenyl,benzonaphthenyl, fluorenyl, 2-acetamidofluoren-9-yl, and4′-bromobiphenyl.

The term “heteroaryl” means an aromatic cyclic or polycyclic ring systemhaving from 1 to 4 heteroatoms selected from N, O, and S. Typicalheteroaryl groups include 2- or 3-thienyl, 2- or 3-furanyl, 2- or3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-,or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl,tetrazolyl, 2-, 3-, or 4-pyridinyl, 3-, 4-, or 5-pyridazinyl,2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-,5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-,5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-,5-, 6-, or 7-benzothiazolyl. The heteroaryl groups may be unsubstitutedor substituted by 1 to 3 substituents selected from those describedabove for alkyl, alkenyl, and alkynyl, for example, cyanothienyl andformylpyrrolyl. Preferred aromatic fused heterocyclic rings of from 8 to10 atoms include but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl-, 2-, 3-, 4-,5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-,5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-,5-, 6-, or 7-benzothiazolyl. Heteroaryl also includes 2- and3-aminomethylfuran, 2- and 3-aminomethylthiophene and the like.

The term “heterocyclic” means a monocyclic, fused, bridged, or spirobicyclic heterocyclic ring systems. Monocyclic heterocyclic ringscontain from about 3 to 12 ring atoms, with from 1 to 5 heteroatomsselected from N, O, and S, and preferably from 3 to 7 member atoms, inthe ring. Bicyclic heterocyclics contain from about 5 to about 17 ringatoms, preferably from 5 to 12 ring atoms. Bicyclic heterocyclic ringsmay be fused, spiro, or bridged ring systems. Examples of heterocyclicgroups include cyclic ethers (oxiranes) such as ethyleneoxide,tetrahydrofuran, dioxane, and substituted cyclic ethers, wherein thesubstituents are those described above for the alkyl and cycloalkylgroups. Typical substituted cyclic ethers include propyleneoxide,phenyloxirane (styrene oxide), cis-2-butene-oxide (2,3-dimethyloxirane),3-chlorotetrahydrofuran, 2,6-dimethyl-1,4-dioxane, and the like.Heterocycles containing nitrogen are groups such as pyrrolidine,piperidine, piperazine, tetrahydrotriazine, tetrahydropyrazole, andsubstituted groups such as 3-aminopyrrolidine, 4-methylpiperazin-1-yl,and the like. Typical sulfur containing heterocycles includetetrahydrothiophene, dihydro-1,3-dithiol-2-yl, andhexahydrothiophen-4-yl and substituted groups such as aminomethylthiophene. Other commonly employed heterocycles includedihydro-oxathiol-4-yl, dihydro-1H-isoindole, tetrahydro-oxazolyl,tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl,hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl,tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl,octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocyclescontaining sulfur, the oxidized sulfur heterocycles containing SO or SO₂groups are also included. Examples include the sulfoxide and sulfoneforms of tetrahydrothiophene.

When a bond is represented by a symbol such as

this is meant to represent that the bond may be absent or presentprovided that the resultant compound is stable and of satisfactoryvalency.

When a bond is represented by a line such as

this is meant to represent that the bond is the point of attachmentbetween two molecular subunits.

The term “patient” means all mammals, including humans. Other examplesof patients include cows, dogs, cats, goats, sheep, pigs, and rabbits.

A “therapeutically effective amount” is an amount of a compound of thepresent invention that, when administered to a patient, provides thedesired effect; i.e., lessening in the severity of the symptomsassociated with a bacterial infection.

It will be appreciated by those skilled in the art that compounds of theinvention having one or more chiral centers may exist in and be isolatedin optically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, geometric, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase) and how to determine activity or cytotoxicity usingthe standard tests described herein, or using other similar tests whichare well known in the art.

Certain compounds of Formula I are also useful as intermediates forpreparing other compounds of Formula I. Thus, a compound wherein R₂ isNR₂, can be metabolized to form another compound of the inventionwherein R₂ is H. This conversion can occur under physiologicalconditions. To that end, both the non-metabolized compound of theinvention and the metabolized compound of the invention—that is, thecompound wherein R₂ is NR₂ and the compound wherein R₂ is H—can haveantibacterial activity.

Some of the compounds of Formula I are capable of further formingpharmaceutically acceptable acid-addition and/or base salts. All ofthese forms are within the scope of the present invention. Thus,pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from nontoxic inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,hydrofluoric, phosphorous, and the like, as well as the salts derivedfrom nontoxic organic acids, such as aliphatic mono- and dicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonicacids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, acetate,trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate,succinates suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzensoulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, and the like. Also contemplated aresalts of amino acids such as arginate and the like and gluconate,galacturonate (see, for example, Berge S. M. et al., “PharmaceuticalSalts,” Journal of Pharmaceutical Science, 1977;66:1-19).

The acid addition salt of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner.

Pharmaceutically acceptable base addition salts are formed with metalsor amines, such as alkali and alkaline earth metals or organic amines.Examples of metals used as cations are sodium, potassium, magnesium,calcium, and the like. Examples of suitable amines areN,N′-dibenzylethylenediaamine, chloroprocaine, choline, diethanolamine,dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine(see, for example, Berge S. M., supra., 1977).

The base addition salts of said acidic compounds are prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

A “prodrug” is an inactive derivative of a drug molecule that requires achemical or an enzymatic biotransformation in order to release theactive parent drug in the body.

Specific and preferred values for the compounds of the present inventionare listed below for radicals, substituents, and ranges are forillustration purposes only, and they do not exclude other defined valuesor other values within defined ranges for the radicals and substituents.

Thus, we turn now to a compound of formula I, which has the structure:

In one embodiment, a specific value for R₁ in a compound of formula I is(C₁-C₆)cycloalkyl and halo(C₁-C₆)cycloalkyl, aryl, or heteroaryl. Aspecifc value for R₂ is NH₂. A specifc value for R₃ is H or NH₂. Aspecific value for R₄ is H or halo. A specific value for R₅ is halo,methyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, ortrifluoromethoxy.

In another embodiment of a compound of formula I, a specific value forR₁ is cyclopropyl, fluorocyclopropyl,

A specifc value for R₂ is NH₂. A specific value for R₃ is H or NH₂. Aspecific value for R₄ is H or F. A specific value for R₅ is halo,methyl, trifluoromethyl, or methoxy.

In another embodiment of a compound of formula I, specific values forR₁, R₂, R₃, and R₅ are as provided in the following structures whereinR₄ is H or F and A is

In another embodiment of a compound of formula I, specific values forR₁, R₂, R₃, and R₅ are as provided in the following structures whereinR₄ is H or F and A is

In one embodiment of compounds of formula I, R_(c), R_(d), R_(f), andR_(g) are H in A, and R_(e) is OPO(OH)₂,

-   -   OPO(O(C₁-C₆)alkyl)₂,    -    wherein    -    indicates the point of attachment and Q is O or is absent,    -    wherein    -    indicates the point of attachment, R_(i) is H or (C₁-C₆)alkyl,        and c is an integer having a value of from 1 to 10,    -   R_(ii)O(C₁-C₆)alkyl,    -   R_(ii)O(C₁-C₆)haloalkyl,    -   R_(ii)O(C₃-C₆)cycloalkyl,    -   R_(ii)O(C₁-C₆)alkyl-O—,    -   R_(ii)O(C₁-C₆)haloalkyl-O—,    -   R_(ii)O(C₃-C₆)cycloalkyl-O—,    -    wherein    -    indicates the point of attachment, het is a 5- or 6-membered        heterocyclo or heteroaryl group, that does not contain an NH,        and x is an integer of from 0 to 10;    -    wherein    -    indicates the point of attachment, het is as defined above, and        y is an integer of from 1 to 10;    -   wherein R_(ii) is H,        -   (C₁-C₆)alkyl,        -   PO(OH)₂,        -   PO(O(C₁-C₆)alkyl)₂,        -    as defined above, or        -    as defined above.

More particularly, when R_(d), R_(e), R_(f), R_(g), and R_(c) aredefined as in the previous paragraph, A is

and includes the following structures, wherein

indicates the point of attachment.

In another embodiment of compounds of formula I, R_(e), R_(f), and R_(g)are H, and R_(c) is OH,

-   -   OPO(OH)₂,    -   OPO(O(C₁-C₆)alkyl)₂,    -    wherein    -    indicates the point of attachment and Q is O or is absent,    -    wherein    -    indicates the point of attachment, R_(i) is H or (C₁-C₆)alkyl,        and c is an integer having a value of from 1 to 10,    -   R_(ii)O(C₁-C₆)alkyl,    -   R_(ii)O(C₁-C₆)haloalkyl,    -   R_(ii)O(C₃-C₆)cycloalkyl,    -   R_(ii)O(C₁-C₆)alkyl-O—,    -   R_(ii)O(C₁-C₆)haloalkyl-O—,    -   R_(ii)O(C₃-C₆)cycloalkyl-O—,    -    wherein    -    indicates the point of attachment, het is a 5- or 6-membered        heterocyclo or heteroaryl group, and x is an integer of from 0        to 10;    -    wherein    -    indicates the point of attachment, het is as defined above, and        y is an integer of from 1 to 10;    -   wherein R_(ii) is H,        -   (C₁-C₆)alkyl,        -   PO(OH)₂,        -   PO(O(C₁-C₆)alkyl)₂,        -    as defined above; and    -   R_(d) is halo,        -   (C₁-C₆)alkyl,        -   R_(ii)O(C₁-C₆)alkyl,        -   R_(ii)O(C₁-C₆)haloalkyl,        -   R_(ii)O(C₃-C₆)cycloalkyl,        -   R_(ii)O(C₁-C₆)alkyl-O—,        -   R_(ii)O(C₁-C₆)haloalkyl-O—,        -   R_(ii)O(C₃-C₆)cycloalkyl-O—,        -    wherein        -    indicates the point of attachment and Q is O or is absent.

More particularly, when R_(d), R_(e), R_(f), R_(g), and R_(c) aredefined as in the previous paragraph, A is

wherein

indicates the point of attachment, and includes

In another embodiment of compounds of formula I, R_(d), R_(f), and R_(g)are H, in A, and R_(c) is OH,

-   -   OPO(OH)₂,    -   OPO(O(C₁-C₆)alkyl)₂,    -    wherein    -    indicates the point of attachment and Q is O or is absent,    -   R_(ii)O(C₁-C₆)alkyl,    -   R_(ii)O(C₁-C₆)haloalkyl,    -   R_(ii)O(C₃-C₆)cycloalkyl,    -   R_(ii)O(C₁-C₆)alkyl-O—,    -   R_(ii)O(C₁-C₆)haloalkyl-O—,    -   R_(ii)O(C₃-C₆)cycloalkyl-O—,    -    wherein    -    indicates the point of attachment, het is a 5- or 6-membered        heterocyclo or heteroaryl group that does not contain an NH, and        x is an integer of from 0 to 10;    -    wherein    -    indicates the point of attachment, het is as defined above, and        y is an integer of from 1 to 10;    -   wherein R_(ii) is H,        -   (C₁-C₆)alkyl,        -   PO(OH)₂,        -   PO(O(C₁-C₆)alkyl)₂,        -    as defined above; and    -   R_(e) is halo        -   wherein        -    indicates the point of attachment and Q is O or is absent,        -   R_(ii)O(C₁-C₆)alkyl,        -   R_(ii)O(C₁-C₆)haloalkyl,        -   R_(ii)O(C₃-C₆)cycloalkyl,        -   R_(ii)O(C₁-C₆)alkyl-O—,        -   R_(ii)O(C₁-C₆)haloalkyl-O—,        -   R_(ii)O(C₃-C₆)cycloalkyl-O—,        -    wherein        -    indicates the point of attachment, het is a 5- or            6-membered heterocyclo or heteroaryl group that does not            contain an NH, and x is an integer of from 0 to 10;        -    wherein        -    indicates the point of attachment, het is as defined above,            and y is an integer of from 1 to 10;        -   wherein R_(ii) is H,            -   (C₁-C₆)alkyl,            -   PO(OH)₂,            -   PO(O(C₁-C₆)alkyl)₂, or            -    as defined above.

More particularly, when R_(a), R_(b), R_(d), R_(f), and R_(g), aredefined as in the previous paragraph, A is

wherein

indicates the point of attachment, and includes

In another embodiment of compounds of formula I, R_(a), R_(b), R_(d),and R_(g) are H and R_(c) is

-   -   OPO(OH)₂,    -   OPO(O(C₁-C₆)alkyl)₂,    -    wherein    -    indicates the point of attachment and Q is O or is absent,    -   R_(ii)O(C₁-C₆)alkyl,    -   R_(ii)O(C₁-C₆)haloalkyl,    -   R_(ii)O(C₃-C₆)cycloalkyl,    -   R_(ii)O(C₁-C₆)alkyl-O—,    -   R_(ii)O(C₁-C₆)haloalkyl-O—,    -   R_(ii)O(C₃-C₆)cycloalkyl-O—,    -    wherein    -    indicates the point of attachment, het is a 5- or 6-membered        heterocyclo or heteroaryl group that does not contain an NH, and        x is an integer of from 0 to 10;    -    wherein    -    indicates the point of attachment, het is as defined above, and        y is an integer of from 1 to 10,    -   wherein R_(ii) is H,        -   (C₁-C₆)alkyl,        -   PO(OH)₂,        -   PO(O(C₁-C₆)alkyl)₂,        -    as defined above; and    -   R_(e) and R_(f) are each independently (C₁-C₆)alkyl or together        with the carbon to which they are attached, form a substituted        or unsubstituted 3, 4, 5, or 6-membered ring containing 0, 1, 2,        or 3 heteroatoms selected from NH, N(C₁-C₆)alkyl, S, or O.

More particularly, when R_(c), R_(e), R_(f) are defined as in theprevious paragraph, A is

wherein

indicates the point of attachment, and includes

In another embodiment of compounds of formula I,

-   -   R_(d) and R_(f) are each independently H,        -   halo        -   (C₁-C₆)alkyl,        -   OH,        -   OPO(OH)₂,        -   OPO(O(C₁-C₆)alkyl)₂,        -    wherein        -    indicates the point of attachment and Q is O or is absent,        -    wherein        -    indicates the point of attachment, R_(i) is H or            (C₁-C₆)alkyl, and c is an integer having a value of from 1            to 10,        -   R_(ii)O(C₁-C₆)alkyl,        -   R_(ii)O(C₁-C₆)haloalkyl,        -   R_(ii)O(C₃-C₆)cycloalkyl,        -   R_(ii)O(C₁-C₆)alkyl-O—,        -   R_(ii)O(C₁-C₆)haloalkyl-O—,        -   R_(ii)O(C₃-C₆)cycloalkyl-O—,        -    wherein        -    indicates the point of attachment, het is as defined above,            and y is an integer of from 1 to 10;        -   wherein R_(ii) is H,            -   (C₁-C₆)alkyl,            -   PO(OH)₂,            -   PO(O(C₁-C₆)alkyl)₂,            -    as defined above;    -   R_(c) and R_(e), together with the carbons to which they are        attached, form a substituted or unsubstituted 4, 5, or        6-membered ring containing 0, 1, 2, or 3 heteroatoms selected        from NH, N(C₁-C₆)alkyl), NH, N(C₁-C₆)alkyl, S, or O.

More particularly, when R_(c) and R_(e), and R_(d) and R_(f) are definedas in the previous paragraph, A is

wherein

indicates the point of attachment, and includes

Preparation of Invention Compounds

Strategies for the preparation of invention compounds are depicted inScheme I, and more specifically in subsequent schemes.

As is readily apparent from this disclosure, compounds of the presentinvention are characterized by a quinazolinedione core, covalently boundto an hydroxylated pyrrolidinyl C-7 sidechain. As retrosyntheticallydepicted in Scheme I, the invention compounds can be prepared viacoupling of a suitably C-7 substituted quinazolinedione core precursor,wherein X is halo, triflate, or a similar reactive group known to theskilled artisan, and is an appropriately substituted pyrrolidine

Reflecting the synthetic strategy summarized in Scheme I, the followingsection describing the preparation of the invention compounds hasseveral parts. The first part describes the synthesis of the requisitequinolone core precursors. The second part describes the synthesis ofthe requisite C-7 sidechain precursors. The final part describes thecoupling of the C-7 sidechain and quinolone core precursors to providethe invention compounds, and details any further chemical elaboration ofinvention compounds to produce other invention compounds.

A. Synthesis of Quinazolinedione Core Precurors

The quinazolinedione core precursors that are used to prepare theinvention compounds can be prepared as described in WO/02 102793,priority date Jun. 19, 2001 and WO/01 53273, priority date Oct. 18,2000, and references cited therein.B. Synthesis of Hydroxylated C-7 Sidechain Precurors

1. Preparation of

The sidechain precursor

as the S stereoisomer was prepared asymmetrically as depicted inScheme 1. S-1 phenyl ethyl amine was used as a chiral protecting groupin the aldehyde reduction. Deprotection 1-2 of provded the requisiteside chain precursor as a 1:1 mixture of diastereomers which werechromatographically separated.

The sidechain precursor

was prepared as depicted in Scheme 2. In the racemic variant,1-benzyl-pyrrolidine-3-carboxylic acid ethyl ester 2-1 was converted tothe Weinreb amide 2-2. After a protecting group exchange, ketoneformation, reduction, and deprotection provided the target compound.

The sidechain precursor

wherein Q is H or F, was prepared as depicted in Scheme 3.R-1-phenyl-ethylamine was converted to the pyrrolidin-2-one upontreatment with 4-chloro-butyryl chloride in the presence of base.Alkylation of 3-2 using lithium diisopropylamide (LDA) anddifluoro-acetic acid ethyl ester provided ketone 3-3. Zinc borohydridereduction of the ketone moiety in 3-3, provided the alcohol 3-4.N,N′-Dicyclohexylcarbodiimide (DCC)-mediated coupling of 34 toBOC-alanine, provided 3-5. Alane reduction of the amide moiety, followedby deprotection and hydrogenation, provided the requisite sidechainprecursor.

The sidechain precursor

was prepared as depicted in Scheme 4. Base mediated benzylation ofbut-3-ene-1,2-diol provided compound 4-2. Oxidation of the hydroylmoiety in 4-2 using the Dess-Martin reagent (triacetoxyperiodinane)provided the vinyl ketone 4-3. Compound 4-3 was converted to pyrrolidine4-5 via [3+2] cycloadditon of the vinyl ketone moiety with theazomethine ylide derived frombenzyl-methoxymethyl-trimethylsilanylmethyl-amine. CsF-catalyzedtrifluoromethylation of the ketone moiety in 4-5 with TMS-CF₃ followedby deprotection provided the requisite sidechain in two additionalsteps, see, e.g., Singh, R. P.; Cao, G.; Kirchmeier, R. L.; Shreeve, J.M. J. Org. Chem. 1999, 64, 2873-2876.

The sidechain precursor

was prepared as depicted in Scheme 5. Thus,5-hydroxymethyl-5H-furan-2-one was prepared according to Nagaoka,Iwashima, Abe, Yamada Tet. Lett. (1989), 30, 5911-5914 and wassubsequently protected as the triisopropyl silyl ether.5-Triisopropylsilanyl oxymethyl-5H-furan-2-one was converted to5-Triisopropylsilanyloxymethyl 4-nitromethyl-dihydro-furan-2-one underconventional conditions. 5-Triisopropylsilanyloxymethyl-4-nitromethyl-dihydro-furan-2-one was hydrogenated to provide4R-Aminomethyl-5S-triisopropylsilanyloxymethyl-dihydro-furan-2-one.Treatment of4R-Aminomethyl-5S-triisopropylsilanyloxymethyl-dihydro-furan-2-one withbase provided4R-(1-hydroxy-2-triisopropylsilanyloxymethyl-ethyl)-pyrrolidin-2-one,which was converted to the target compound in a straightforward manner.

The sidechain precursor

was prepared as indicated in Scheme 6. Steps 1-5 are identical to steps1-5 in Scheme 5. Reduction provided the requisite sidechan precursor.

The sidechain precursor

was prepared as indicated in Scheme 7. Similar to Scheme 4, ethylacrylate 7-1 was converted to pyrrolidine 7-3 via [3+2] cycloadditonwith the azomethine ylide derived frombenzyl-methoxymethyl-trimethylsilanylmethyl-amine. Compound 7-3 wasconverted to the cyclopropanol 7-4 upon treatment with ethylmagnesiumbromide in the presence of Ti(O-iPr)₄. Deprotection provided therequisite compound.

The sidechain precursor

was prepared as indicated in Scheme 8. Thus,1-hydroxy-cyclopropanecarboxylic acid ethyl ester (8-1) was protected asthe tertbutyldimethylsilyl (TBDMS) ether, then underwent reaction withthe anion of lactam 8-3 to provide the alkylation product 8-4. Reductionof the carbonyl moieties in 84 followed by a sequence of protection anddeprotection reactions, provided the requisite sidechain precursor.

The sidechain precursor

was prepared upon hydrogenation of compound 9-1 as indicated in Scheme9.

The sidechain precursor

was prepared as indicated in Scheme 10. Thus, reduction of compound 10-1provided alcohol 10-2, which underwent hydrogenation to provided therequisite side chain precursor.

The sidechain precursor

was prepared as indicated in Scheme 11. Thus, LDA-mediated alkylation oflactam 11-1 with cyclopropane-1,1-dicarboxylic acid diethyl esterprovided diketoester 11-3. Reduction of compound 11-3 using LAH andaluminum trichloride (AlCl₃) provided alcohol 11-4, which underwenthydrogenation to provided the requisite sidechain precursor.

The sidechain precursor

was prepared as indicated in Scheme 12. Thus, 5-nitro-furan-2-carboxylicacid 12-1 was converted to the ethyl ester 12-2 under conventionalconditions. Compound 12-2 was converted to the thioether 12-3 uponheating in the presence of NaSMe. Thioether 12-3 was oxidized to thesulfone 124 using m-chloroperbenozic acid (mCPBA). LDA-mediatedalkylation of lactam 11-1 with sulfone 12-4 provided the requisitesidechain precursor 12-5 which was converted to 12-9 under standardconditions.

The sidechain precursor

was prepared as indicated in Scheme 13. Thus,1-hydroxy-cyclopropanecarboxylic acid ethyl ester 13-1 was protected asthe TBDMS ether 13-2, and then allowed to undergo reaction with theanion of lactam 11-1 to provide the alkylation product 13-3. Reductionof the carbonyl moieties in 13-3, followed by a sequence of protectionand deprotection reactions, provided the requisite sidechain precursor.

The sidechain precursur

was prepared as indicated in Scheme 14. Thus, ketone 14-1 was convertedto the gem-difluoride 14-2 upon treatment with diethylaminosulfurtrifluoride. Hydrogenation of compound 14-2 under standard conditionsprovided the requisite sidechain.

The sidechain precursor

was prepared as indicated in Scheme 15. Thus, compound 15-1 was preparedaccording to Org. Syn. Coll. Vol. IV, p. 298. Similar to Scheme 7,acrylate 15-3 was converted to pyrrolidine 15-4 via [3+2] cycloadditonwith the azomethine ylide derived frombenzyl-methoxymethyl-trimethylsilanylmethyl-amine, followed by reductionof the resulting diester. Compound 15-4 was converted to the requisitesidechain precursor upon deprotection.

The sidechain precursor

was prepared as indicated in Scheme 16. Thus, diester 16-1 was reducedto the diol 16-2, which was hydrogenated under conventional condtions toprovide the requisite sidechain precursor.

The sidechain precursor

can be prepared as indicated in Scheme 17. Thus, the isoindole 17-1 canbe benzylated to provide 17-2. Oxidative cleavage of 17-2 using areagent known to the skilled artisan such as permanganate (MnO₄) or byozonlysis can provide dialdehyde 17-3, which is readily reduced to thediol 17-4. Reduction of the imide moiety in 17-4 and deprotectionprovides the requisite sidechain precursor.

The sidechain precursor

was prepared as indicated in Scheme 18. Thus, [3+2] cycloaddition of thecis maleate 18-1 with the azomethine ylide derived form compound 15-2provided pyrrolidine 18-2. Reduction of the ester moieties in 18-2,followed by deprotection, provided the requisite sidechain precursor.

The sidechain precursor

was prepared as indicated in Scheme 19. Thus, similar to Scheme 18,[3+2] cycloaddition of the trans maleate 19-1 with the azomethine ylidederived from compound 15-2 provided pyrrolidine 19-2. Reduction of theester moieties in 19-2, followed by silylation of the resulting diol anddeprotection, provided 19-5, which can be converted to the free diolupon deprotection.

The sidechain precursor

was prepared as indicated in Scheme 20. Thus, osmium tetroxide(OsO₄)-catalyzed hydroxylation of the double bond in compound 20-1provided the cis diol 20-2, which was converted to the requisitesidechain precursor upon deprotection.

The sidechain precursor

was prepared as indicated in Scheme 21. Thus, similar to Scheme 18,[3+2] cycloaddition of the 4-Methyl-pent-3-en-2-one with the azomethineylide derived form compound 21-1 provided pyrrolidine 21-2. Compound21-2 was converted to the CBZ amide 21-3. Reduction of the ketone moietyin 21-4, followed by deprotection, provided the requisite sidechainprecursor.

The sidechain precursor

was prepared as provided in Scheme 22. Thus [3+2] cycloaddtion of3,4-dimethyl-furan-2,5-dione with the azomethine ylide derived formcompound 15-2 provided pyrrolidine 22-1. Hydrogenation of 22-1 understandard conditions afforded the requisite sidechain precursor.

The sidechain precursor

was prepared as indicated in Scheme 23. Thus, [3+2] cycloaddition ofcyclopent-2-enone with the azomethine ylide derived from compound 15-2provided pyrrolidine 23-1. Compound 23-1 was deprotected, thenreporotected as the CBZ amide 23-2. SmI₂-catalyzed hydroxymethylation of23-2 provided hydroxy ether 23-3, see, e.g., Imamoto, T.; Takeyama, T.;Yokoyama, M. Tetrahedron Letters, 1984, 25, 3225-3226. Removal of theprotecting groups by hydrogenation provided the requisite sidechainprecursor.

The sidechain precursor

was prepared as indicated in Scheme 24. Compound 23-2 was prepared asindicated in Scheme 23. L-Selectride reduction of the ketone moiety incompound 23-2 provided alcohol 24-1, see, e.g., Ogata, M.; Matsumoto,H.; Shimizu, S.; Kida, S.; Nakai, H.; Motokawa, K.; Miwa, H.; Matsuura,S.; Yoshida, T. Eur. J. Med. Chem. 1991, 26, 889-906. Syn elimination ofthe hydroxy moiety in compound 24-1 using the Burgess reagent providedcompound 24-2 see, e.g., Campbell, E.; Martin, J. J.; Bordner, J.;Kleinman, E. F. J. Org. Chem. 1996, 61, 4806-4809. Yamada, O.;Ogasawara, K. Tetrahedron Letters 1998, 39, 7747-7750. OSO₄-catalyzedhydroxylation of the double bond in compound 24-2 provided the cis diol24-3, which was converted to the requisite sidechain precursor upondeprotection.

The sidechain precursor

was prepared as indicated in Scheme 25. Compound 24-1 was prepared asindicated in Scheme 24. Deprotection of compound 24-1 provided therequisite sidechain precursor.

The sidechain precursor

was prepared as indicated in Scheme 26. Compound 24-1 was prepared asindicated in Scheme 24. Mitsunobu reaction of the alcohol moiety incompound 24-1 provided the ester 26-1, see, e.g., Jeong, L. S.; Yoo, S.J.; Moon, H. R.; Kim, Y. H.; Chun, M. W. J. Chem. Soc., Perkin Trans. 11998, 3325-3326. Ester 26-1 was saponified under conventional conditionsto provided compound 26-2. Deprotection of compound 26-2 provided therequisite sidechain precursor.

The sidechain precursors

were prepared as indicated in Scheme 27. Compound 23-2, prepared asindicated in Scheme 23, was converted to the silyl enol ether 27-1 underconventional conditions. Concomittant desilylation and fluorinationprovided fluorides 27-2a and 27-2b as a separatable mixture ofdiastereomers. Diastereomers 27-2a and 27-2b were reduced usingL-Selectride to provide alcohols 27-3a and 27-3b, which were deprotectedto provided the requisite sidechains.

The sidechain precursor

was prepared as indicated in Scheme 28. Compound 28-1 underwentMitsunobu reaction to provide ester 28-2, which underwenttransesterification and deprotection to provide the requisite sidechain.

Similarly, as indicated in Scheme 29, the sidechain precursor

was prepared via the same sequence of reactions as provided in Schemes27 and 29. Compound 29-1 underwent Mitsunobu reaction to provide ester29-2, which underwent transesterification and deprotection to providethe requisite sidechain.

Sidechain precursor

was prepared as provided in Scheme 31 from the diasteromeric mixture ofalpha fluoro ketones obtained in Scheme 27, or from either diastereomeralone. Thus deprotonation and fluorination, see, e.g., Thomas, M. G.;Suckling, C. J.; Pitt, A. R.; Suckling, K. E. J. Chem. Soc., PerkinTrans. 1 1999, 3191-3198, provided difluoroketone 31-1. Reduction ofcompound 31-1, followed by deprotection, provided the requisitesidechain.

The sidechain precursor

was prepared as indiciated in Scheme 32. Thus, [3+2] cycloaddtion of5,6-dihydro-4H-cyclopenta[c]furan-1,3-dione with the azomethine ylidederived from compound 15-2 provided compound 15-1. Hydrogenation of 15-1under standard conditions afforded the requisite sidechain precursor.

C. Coupling of Hydroxylated C-7 Sidechain and Aminoquinazoline DioneCore Precurors to Provide Invention Compounds

The quinazolinedione core precursors that are used to prepare theinvention compounds can be prepared as described in WO/02 102793,priority date Jun. 19, 2001 and WO/01 53273, priority date Oct. 18,2000, and references cited therein.

Pharmaceutical Formulations

The present invention also provides pharmaceutical compositions whichcomprise a bioactive invention compound or a salt such or apharmaceutically acceptable salt thereof and optionally apharmaceutically acceptable carrier. The compositions include those in aform adapted for oral, topical or parenteral use and can be used for thetreatment of bacterial infection in mammals including humans.

The compounds, such as antibiotic compounds, also referred to herein asantimicrobial compounds, according to the invention can be formulatedfor administration in any convenient way for use in human or veterinarymedicine, by analogy with other bioactive agents such as antibiotics.Such methods are known in the art and are not described in detailherein.

The composition can be formulated for administration by any route knownin the art, such as subdermal, by-inhalation, oral, topical orparenteral. The compositions may be in any form known in the art,including but not limited to tablets, capsules, powders, granules,lozenges, creams or liquid preparations, such as oral or sterileparenteral solutions or suspensions.

The topical formulations of the present invention can be presented as,for instance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, suchas cream or ointment bases and ethanol or oleyl alcohol for lotions.Such carriers may be present, for example, from about 1% up to about 98%of the formulation. For example, they may form up to about 80% of theformulation.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrollidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods will known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerine, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavoring or coloring agents.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle or other suitable solvent. Inpreparing solutions, the compound can be dissolved in water forinjection and filter sterilized before filling into a suitable vial orampoule and sealing. Advantageously, agents such as a local anestheticpreservative and buffering agents can be dissolved in the vehicle. Toenhance the stability, the composition can be frozen after filling intothe vial and the water removed under vacuum. The dry lyophilized powderis then sealed in the vial and an accompanying vial of water forinjection may be supplied to reconstitute the liquid prior to use.Parenteral suspensions are prepared in substantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and sterilization cannot be accomplished by filtration. Thecompound can be sterilized by exposure to ethylene oxide beforesuspending in the sterile vehicle. Advantageously, a surfactant orwetting agent is included in the composition to facilitate uniformdistribution of the compound.

The compositions may contain, for example, from about 0.1% by weight,e.g., from about 10-60% by weight, of the active material, depending onthe method of administration. Where the compositions comprise dosageunits, each unit will contain, for example, from about 50-500 mg of theactive ingredient. The dosage as employed for adult human treatment willrange, for example, from about 100 to 3000 mg per day, for instance 1500mg per day depending on the route and frequency of administration. Sucha dosage corresponds to about 1.5 to 50 mg/kg per day. Suitably thedosage is, for example, from about 5 to 20 mg/kg per day.

Biological Activity

The invention compounds can be screened to identify bioactive moleculeswith different biological activities using methods available in the art.The bioactive molecules, for example, can possess activity against acellular target, including but not limited to enzymes and receptors, ora microorganism. A target cellular ligand or microorganism is one thatis known or believed to be of importance in the etiology or progressionof a disease. Examples of disease states for which compounds can bescreened for biological activity include, but are not limited to,inflammation, infection, hypertension, central nervous system disorders,and cardiovascular disorders.

In one embodiment, the invention provides methods of treating orpreventing a bacterial infection in a subject, such as a human or otheranimal subject, comprising administering an effective amount of aninvention compound as disclosed herein to the subject. In oneembodiment, the compound is administered in a pharmaceuticallyacceptable form optionally in a pharmaceutically acceptable carrier. Asused herein, an “infectious disorder” is any disorder characterized bythe presence of a microbial infection, such as bacterial infections.Such infectious disorders include, for example central nervous systeminfections, external ear infections, infections of the middle ear, suchas acute otitis media, infections of the cranial sinuses, eyeinfections, infections of the oral cavity, such as infections of theteeth, gums and mucosa, upper respiratory tract infections, lowerrespiratory tract infections, genitourinary infections, gastrointestinalinfections, gynecological infections, septicemia, bone and jointinfections, skin and skin structure infections, bacterial endocarditis,burns, antibacterial prophylaxis of surgery, and antibacterialprophylaxis in immunosuppressed patients, such as patients receivingcancer chemotherapy, or organ transplant patients. The compounds andcompositions comprising the compounds can be administered by routes suchas topically, locally or systemically. Systemic application includes anymethod of introducing the compound into the tissues of the body, e.g.,intrathecal, epidural, intramuscular, transdermal, intravenous,intraperitoneal, subcutaneous, sublingual, rectal, and oraladministration. The specific dosage of antimicrobial to be administered,as well as the duration of treatment, may be adjusted as needed.

The compounds of the invention may be used for the treatment orprevention of infectious disorders caused by a variety of bacterialorganisms. Examples include Gram positive and Gram negative aerobic andanaerobic bacteria, including Staphylococci, for example S. aureus;Enterococci, for example E. faecalis; Streptococci, for example S.pneumoniae; Haemophilus, for example H. influenza; Moraxella, forexample M. catarrhalis; and Escherichia, for example E. coli. Otherexamples include Mycobacteria, for example M. tuberculosis;intercellular microbes, for example Chlamydia and Rickettsiae; andMycoplasma, for example M. pneumoniae.

The ability of a compound of the invention to inhibit bacterial growth,demonstrate in vivo activity, and enhanced pharmacokinetics aredemonstrated using pharmacological models that are well known to theart, for example, using models such as the tests described below.

Test A—Antibacterial Assays

The compounds of the present invention were tested against an assortmentof Gram-negative and Gram-positive organisms using standardmicrotitration techniques (Cohen et. al., Antimicrob., 1985;28:766;Heifetz, et. al., Antimicrob., 1974;6:124). The results of theevaluation are shown in Tables 1A and B.

Table 1A Minimum Inhibitory Concentrations μg/mL Gram Negative BacteriaH. influenzae M. catarrhalis E. coli Compound HI-3542 BC-3531 EC-2549

0.5 1 4

2 2 32

1 2 16

4 8 64

2 1 16

1 1 8

0.5 1 4

0.125 0.125 2

4 4 32 Table 1B Minimum Inhibitory Concentrations μg/mL Gram PositiveBacteria E. faecalis S. pneumo S. aureus S pyogenes Compound MGH-2 SV-1UC-76 C203

2 1 0.5 2

8 8 0.5 8

8 4 1 4

16 8 2 8

4 2 0.5 4

4 4 0.5 8

2 1 0.25 1

1 0.5 0.06 1

4 2 1 4

Table 2A Minimum Inhibitory Concentrations μg/mL Gram Negative BacteriaH. influenzae M. catarrhalis E. coli Compound HI-3542 BC-3531 EC-2549

0.5 1 16

1 4 32

0.5 2 16

0.015 0.06 0.125

0.5 1 4 Table 2B Minimum Inhibitory Concentrations μg/mL Gram PositiveBacteria E. Compound Structure or faecalis S. pneumo S. aureus Spyogenes Example No. MGH-2 SV-1 UC-76 C203

4 2 0.25 1

8 4 0.5 2

8 8 2 8

0.06 0.03 0.002 0.03

4 2 0.25 4

Table 3A Minimum Inhibitory Concentrations μg/mL Gram Negative BacteriaH. influenzae M. catarrhalis E. coli Compound HI-3542 BC-3531 EC-2549

16 32 64 Table 3B Minimum Inhibitory Concentrations μg/mL Gram PositiveBacteria E. faecalis S. pneumo S. aureus S pyogenes Compound MGH-2 SV-1UC-76 C203

16 16 2 32

VII

Table 4A Minimum Inhibitory Concentrations μg/mL Gram Negative BacteriaH. influenzae M. catarrhalis E. coli Compound HI-3542 BC-3531 EC-2549

4 4 32 Table 4B Minimum Inhibitory Concentrations μg/mL Gram PositiveBacteria E. faecalis S. pneumo S. aureus S pyogenes Compound MGH-2 SV-1UC-76 C203

8 8 1 8

The following examples are provided to illustrate but not limit theclaimed invention.

A. Synthesis of Sidechain Precursors

EXAMPLE 1 Preparation of3,3,3-Trifluoro-2-pyrrolidin-3-yl-propane-1,2-diol

Step 1: Preparation of 1-Benzyloxy-but-3-en-2-ol

To a cooled (0° C.) solution of 3,4-dihydroxy-1-butene (9.9 mL, 118mmol) in tetrahydrofuran (400 mL) was added sodium hydride (NAH) (5.7 g,142 mmol, 60% dispersion in mineral oil) portionwise over 20 minutes.The resulting white slurry was allowed to stir for 30 minutes, andbenzyl bromide (16.8 mL, 142 mmol) was added, followed bytetrabutylammonium iodide (8.7 g, 24 mmol). The reaction mixture waswarmed to room temperature and was then heated at 70° C. for 24 hours.The mixture was concentrated in vacuo, and the resulting residue waspartitioned between saturated aqueous ammonium chloride anddichloromethane. The aqueous layer was extracted three times withdichloromethane, and the combined organics were dried over magnesiumsulfate, filtered, and concentrated in vacuo. The resulting residue waspurified on a 65M Biotage column using an ethyl acetate/hexanes gradientto afford the title compound (11.6 g, 55%) as a clear oil. ¹H NMR(CDCl₃): δ 2.45 (m, 1H), 3.38 (dd, J=9.5, 7.9 Hz, 1H), 3.54 (dd, J=9.5,3.4 Hz, 1H), 4.35 (m, 1H), 4.58 (s, 2H), 5.34 (m, 1H), 5.38 (m, 1H),5.82 (m, 1H), 7.38-7.29 (m, 5H).

Step 2: Preparation of 1-Benzyloxy-but-3-en-2-one

To a solution of 1-benzyloxy-but-3-en-2-ol product (8.0 g, 45 mmol) andDess-Martin periodinane (23 g, 54 mmol) in dichloromethane (140 mL) wasadded water (0.89 mL, 49 mmol) in dichloromethane (30 mL) over 30minutes. After 1.5 hours, the white slurry was diluted with diethylether and filtered through a pad of diatomaceous earth (Celite®). Thefiltrate was washed with a 1:1 mixture of saturated aqueous sodiumbicarbonate and 0.1N sodium thiosulfate, dried over magnesium sulfate,filtered, and concentrated in vacuo to give the title compound (7.6 g,96%) as a yellow liquid which was used without further purification. ¹HNMR (CDCl₃): δ 4.27 (s, 2H), 4.61 (s, 2H), 5.82 (dd, J=10.7, 1.5 Hz,1H), 6.34 (dd, J=17.6, 1.5 Hz, 1H), 6.55 (dd, J=17.6, 10.7 Hz, 1H), 7.33(m, 5H).

Step 3: Preparation of 2-Benzyloxy-1-(1-benzyl-pyrrolidin-3-yl)-ethanone

To a cooled (0° C.) solution of 1-(phenylmethoxy)-3-butene-2-one (7.6 g,43 mmol) and benzyl-1-methoxymethyl-1-trimethylsilylmethyl amine (15 g,65 mmol) in dichloromethane (105 mL) was added trifluoroacetic acid (3mL, 1.0 M in dichloromethane). The reaction mixture was allowed toslowly warm to room temperature over 18 hours. The mixture was dilutedwith dichloromethane and saturated aqueous sodium bicarbonate. Theaqueous layer was extracted two times with dichloromethane, and thecombined organics were washed with saturated aqueous sodium bicarbonate,brine, dried over magnesium sulfate, filtered, and concentrated invacuo. The residue was purified on a 40L Biotage column using an ethylacetate/dichloromethane gradient to afford the title compound (5.0 g,37%) as a yellow oil. MS(APCI+): m/z 310.1 (M+H)⁺.

Step 4: Preparation of3-Benzyloxy-2-(1-benzyl-pyrrolidin-3-yl)-1,1,1-trifluoro-propan-2-ol

To a mixture of 2-benzyloxy-1-(1-benzyl-pyrrolidin-3-yl)-ethanone (5.0g, 16 mmol) and 4 angstrom molecular sieves was addedtrimethyl(trifluoromethyl) silane (65 mL, 32 mmol, 0.5 M intetrahydrofuran), and the slurry was stirred at room temperature for 10minutes. Cesium fluoride (1.2 g, 8.1 mmol) was added, and the reactionmixture was stirred for 56 hours. Tetrabutylammonium fluoride (32 mL, 32mmol, 1 M in tetrahydrofuran) was added and after 5 hours, the mixturewas concentrated in vacuo, and the resulting residue was taken up indichloromethane and filtered through a pad of diatomaceous earth(Celite®). The organic layers were combined, washed with saturatedaqueous sodium bicarbonate, brine, dried over magnesium sulfate,filtered, and concentrated in vacuo. The residue was purified on a 65MBiotage column using an ethyl acetate/dichloromethane gradient to affordthe title compound (3.3 g, 55%) as an orange oil. MS(APCI+): m/z 380.2(M+H)⁺, 378.1 (M−H)⁺.

Step 5: Preparation of3,3,3-Trifluoro-2-pyrrolidin-3-yl-propane-1,2-diol

To a solution of3-Benzyloxy-2-(1-benzyl-pyrrolidin-3-yl)-1,1,1-trifluoro-propan-2-ol(3.3 g, 8.7 mmol) in tetrahydrofuran (50 mL) and methanol (50 mL) in aParr shaker was added 20% palladium hydroxide on carbon (2.5 g), andhydrogen gas was introduced at 37 psi for 18 hours. The reaction mixturewas diluted with methanol, filtered through diatomaceous earth(Celite®), and concentrated in vacuo to afford the title compound (1.5g, 87%) as an orange oil which was used without further purification.MS(APCI+): m/z 200.0 (M+H)⁺.

EXAMPLE 2 Preparation of 2-Pyrrolidin-3-yl-propane-1,2-diol

Step 1: Preparation of 1-Benzyl-pyrrolidine-3-carboxylic Acidmethoxy-methyl-amide

To a cooled (0° C.) solution of N,O-dimethylhydroxylamine hydrochloride(3.7 g, 38 mmol) in dichloromethane (120 mL) was added dimethylaluminumchloride (38 mL, 38 mmol, 1.0 M in hexanes) dropwise. The reactionmixture was warmed to room temperature, and after 1 hour,1-benzylpyrrolidine-3-carboxylic acid ethyl ester (3.0 g, 13 mmol) indichloromethane (40 mL) was added. The transfer was completed with 10 mLof dichloromethane. After 18 hours, the reaction mixture was poured into150 mL of cold (0° C.) 1 M potassium carbonate (pH 13). The slurry wasstirred at 0° C. for 1 hour, room temperature for 2 hours, and filteredthrough a pad of diatomaceous earth (Celite®) using chloroform as theeluent. The aqueous layer was removed, and the organics were dried overmagnesium sulfate, filtered, and concentrated in vacuo to afford thetitle compound (2.9 g, 91%) as an orange oil which was used withoutfurther purification. MS(APCI+): m/z 249.2 (M+H)⁺.

Step 2: Preparation of3-(Methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic Acid Benzyl Ester

To a solution of 1-benzyl-pyrrolidine-3-carboxylic acidmethoxy-methylamide (1.1 g, 4.4 mmol) in dichloromethane (40 mL) wasadded benzyl chloroformate (1.1 mL, 7.5 mmol). The reaction mixture wasstirred at room temperature for 4 hours and was then concentrated invacuo. The resulting residue was purified on a 40L Biotage column usingan ethyl acetate/hexanes gradient to afford the title compound (0.91 g,71%) as a clear liquid. MS(APCI+): m/z 293.1 (M+H)⁺.

Step 3: Preparation of 3-Acetyl-pyrrolidine-1-carboxylic Acid BenzylEster

To a cooled (−78° C.) solution of3-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester(2.8 g, 9.6 mmol) in tetrahydrofuran (50 mL) was added methyllithium(9.0 mL, 14 mmol, 1.6 M in diethyl ether) dropwise. After 1 hour, thereaction mixture was warmed to room temperature and diluted withsaturated aqueous ammonium chloride and ethyl acetate. The aqueous layerwas extracted two times with ethyl acetate, and the combined organicswere washed with brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was purified on a 40S Biotage columnusing an ethyl acetate/hexanes gradient to afford the title compound(2.1 g, 89%) as a yellow oil. MS(APCI+): m/z 248.1 (M+H)⁺.

Step 4: Preparation of 3-Acetyl-pyrrolidine-1-carboxylic Acid BenzylEster

To a mixture of 3-acetyl-pyrrolidine-1-carboxylic acid benzyl ester (2.3g, 9.3 mmol) and benzyl chloromethyl ether (2.6 mL, 11 mmol, 60%technical grade) was added samarium iodide (280 mL, 28.0 mmol, 0.1 M intetrahydrofuran). The dark blue reaction mixture was stirred at roomtemperature for 3 hours, during which time it turned bright yellow. Themixture was diluted with saturated aqueous ammonium chloride and ethylacetate. The aqueous layer was extracted two times with ethyl acetate,and the combined organics were washed with brine, dried over magnesiumsulfate, filtered, and concentrated in vacuo. The residue was purifiedon a 40M Biotage column using an ethyl acetate/hexanes gradient toafford the title compound (1.2 g, 35%) as a pale yellow oil. MS(APCI+):m/z 370.1 (M+H)⁺.

Step 5: Preparation of 3-Acetyl-pyrrolidine-1-carboxylic Acid BenzylEster

To a solution of 3-acetyl-pyrrolidine-1-carboxylic acid benzyl ester(0.60 g, 1.6 mmol) in ethanol (16 mL) in a Parr shaker was added 20%palladium hydroxide on carbon (0.66 g), and hydrogen gas was introducedat 37 psi for 130 hours. The reaction mixture was diluted with methanol,filtered through diatomaceous earth (Celite®), and concentrated in vacuoto afford the title compound (0.24 g, 100%) as an orange oil which wasused without further purification. MS(APCI+): m/z 146.1 (M+H)⁺.

EXAMPLE 3 1-Pyrrolidin-3-yl-ethanol

Step 1: Preparation of 1-Benzyl-pyrrolidine-3-carboxylic Acidmethoxy-methyl-amide

To methoxymethylamine hydrochloride (3.74 g, 38 mmol) in dichloromethane(120 mL) at 0° C. was added dimethylaluminum chloride (38 mL, 38 mmol)via addition funnel. The reaction was warmed to room temperature andstirred for 1 hour. 1-benzyl-pyrrolidine-3-carboxylic acid ethyl ester(3.0 g, 12.8 mmol) in dichloromethane (40 mL) was added and after 12hours, the mixture was poured into 1M potassium carbonate solution (150mL) at 0° C., stirred at 0° C. for 1 hour, then at room temperature for2 hours. The mixture was filtered through celite, and extracted withchloroform. The organic layer was dried over magnesium sulfate,filtered, and concentrated in vacuo to give the title compound (Yield:2.9 g) which was used in the next step without further purification.

Step 2: Preparation of 3-Acetyl-pyrrolidine-1-carboxylic Acid BenzylEster

To a solution of 1-benzyl-pyrrolidine-3-carboxylic acidmethoxy-methylamide (240 mg, 0.97 mmol) in dichloromethane (10 mL) wasadded carboxybenzyloxychloride (0.23 mL, 1.64 mmol). After stirring atroom temperature for 1.5 hours, the reaction mixture was concentratedand the crude residue was purified by column chromatography (0 to 100%ethyl acetate in dichloromethane) to afford the requisite CBZintermediate (Yield: 120 mg, 43%) which was used in the next stepwithout further purification.

To a solution of the CBZ intermediate (2.8 g, 9.6 mmol) intetrahydrofuran (50 mL) at −78° C. was added methyl lithium (9 mL of a1.6M solution in ether) dropwise by syringe. After 1 hour, the reactionmixture was warmed to room temperature, quenched with saturated aqueousammonium chloride solution and extracted with ethyl acetate. The organiclayer was washed with brine, dried over magnesium sulfate, filtered, andconcentrated to afford a crude residue which was purified by columnchromatography (0 to 100% ethyl acetate in hexanes) to afford the titlecompound (Yield: 2.1 g, 89%) which was used without further purificationin the next step.

Step 3: Preparation of 3-(1-Hydroxy-ethyl)-pyrrolidine-1-carboxylic AcidBenzyl Ester

To a solution of 3-Acetyl-pyrrolidine-1-carboxylic acid benzyl ester(1.4 g, 5.7 mmol) in methanol (30 mL) at 0° C. was added sodiumborohydride (0.32 g, 8.5 mmol). After 2 hours, the reaction was quenchedwith saturated ammonium chloride solution and extracted withdichloromethane. The organic layer was dried over magnesium sulfate,filtered, and concentrated. The crude residue was purified by columnchromatography (30 to 50% ethyl acetate in hexanes) to afford the titlecompound as a 2:1 mixture of diastereomers (Yield: 1.0 g, 71%).MS(APCI+): m/z 250 (M+H)+.

Step 4: Preparation of 1-Pyrrolidin-3-yl-ethanol

To a solution of 3-(1-hydroxy-ethyl)-pyrrolidine-1-carboxylic acidbenzyl ester (1.0 g, 4.0 mmol) in methanol (50 mL) was added 20% Pd/C.The reaction was stirred under an atmosphere of hydrogen for 12 hours.The reaction was filtered and concentrated to give the title compound(Yield: 426 mg, 92%). MS(APCI+): m/z 116 (M+H)+.

EXAMPLE 4 2,2-Difluoro-1S-pyrrolidin-3R-yl-ethanol

Step 1: Preparation of 1-(1R-Phenyl-ethyl)-pyrrolidin-2-one

R-(+)-α-methylbenzylamine (100 g, 825 mmol), methylene chloride (330mL), and sodium hydroxide (26 g, 907 mmol) in water (412 mL) wereintroduced into a 3 liter 3-necked round bottom flask which wasmechanically stirred and equipped with a 250 mL dropping funnel andthermometer. The mixture was cooled in an ice bath while stirringvigorously. 4-Chlorobutyryl chloride (92 mL, 825 mmol) indichloromethane (80 mL) was added dropwise keeping the temperature under10° C. The reaction mixture was stirred vigorously for 15 minutes, andtransferred to a 2 liter separatory funnel. The dichloromethane layerwas transferred into a 2 liter 3-necked round bottom flask containingbenzyltriethylammonium chloride (9.4 g, 41 mmol) to which a 50% solutionof sodium hydroxide in water (330 mL) was added rapidly. The mixture wasstirred vigorously then heated at reflux for 2 hours. Water was addedand the dichloromethane layer was drawn off. The aqueous layer was backextracted 2× and the combined organic layers were washed with 1N HClfollowed by water. The organic layer was dried over magnesium sulfate,filtered and concentrated to give the title compound (Yield: 155 g, 99%)which was used in the next step without further purification.

Step 2: Preparation of3-(2,2-Difluoro-acetyl)-1-(1R-phenyl-ethyl)-pyrrolidin-2-one

To a solution of 1-(1R-phenyl-ethyl)-pyrrolidin-2-one (23.2 g, 123 mmol)in tetrahydrofuran (300 mL) at −78° C. was added lithiumdiisopropylamide (74 mL of a 2M solution inheptane/tetrahydrofuran/ethyl benzene). The reaction stirred for 1 hour40 minutes. This solution was added via cannula to a solution of ethyldifluoroacetate (16 mL, 160) in tetrahydrofuran (100 mL). After 1 hour,the reaction was quenched by the addition of saturated aqueous ammoniumchloride solution. The reaction was warmed to room temperature andconcentrated to remove the tetrahydrofuran. The mixture was diluted withwater and extracted with ethyl acetate. The organic layer was dried overmagnesium sulfate, filtered and concentrated. The crude residue waspurified by column chromatography (20% ethyl acetate in hexanes) toafford the title compound (Yield: 20.9 g, 64%) which was used in thenext step without further purification.

Step 3: Preparation of3-(2,2-Difluoro-1-hydroxy-ethyl)-1-(1R-phenyl-ethyl)-pyrrolidin-2-one

To a solution of3-(2,2-Difluoro-acetyl)-1-(1R-phenyl-ethyl)-pyrrolidin-2-one (19.6 g,73.4 mmol) in ether (200 mL) at 0° C. was added a solution of zincborohydride (100 mmol) in ether (200 mL) via cannula. The reactionwarmed to room temperature overnight. The reaction was quenched by thedropwise addition of saturated aqueous ammonium chloride solution. Themixture was extracted with ethyl acetate and the organic layer was driedover magnesium sulfate, filtered and concentrated. The crude residue waspurified by column chromatography (30 to 40% ethyl acetate in hexanes)to give a mixture of diastereomers 1 and 2 (Yield: 8.7 g, 44%) and amixture of diastereomers 3 and 4 (Yield 4.7 g, 24%). Diastereomers 1 and2 were carried into the next step without further purification.

Step 4: Preparation of BOC Valine-Protected3-(2,2-Difluoro-1-hydroxy-ethyl)-1-(1R-phenyl-ethyl)-pyrrolidin-2-one

To a solution of3-(2,2-difluoro-1-hydroxy-ethyl)-1-(1R-phenyl-ethyl)-pyrrolidin-2-one(6.0 g, 22.3 mmol), boc-L-valine (9.7 g, 44.6 mmol), andN,N-dimethylaminopyridine (272 mg, 2.23 mmol) in dichloromethane (100mL) at 0° C. was added dicyclohexyl carbodiimide (17.5 g, 84.8 mmol).The reaction mixture stirred for 2 hours. The solid was filtered off,and the filtrate was poured into a solution of saturated sodiumbicarbonate solution and extracted with dichloromethane. The organiclayer was dried over magnesium sulfate, filtered and concentrated. Thecrude residue was purified by column chromatography (10 to 40% ethylacetate in hexanes) to afford diastereomer 2 (Yield 4.9 g, 47%) andDiastereomer 1 (Yield: 4.3 g, 41%) Diastereomer 1 was used in the nextstep without further purification.

Step 5: Preparation of2,2-Difluoro-1S-[1-(1R-phenyl-ethyl)-pyrrolidin-3R-yl]-ethanol

To aluminum chloride (7.3 g, 54.5 mmol) at 0° C. was addedtetrahydrofuran (30 mL) dropwise. After 5 minutes, lithium aluminumhydride (163 mL of a 1M solution in tetrahydrofuran) was added. Thesolution of alane was warmed to room temperature and stirred for 20minutes, cooled to −78° C., and a solution of2,2-difluoro-1S-[1-(1R-phenyl-ethyl)-pyrrolidin-3R-yl]-ethanol (17 g,36.3 mmol) in tetrahydrofuran (60 mL) was added. The reaction warmed toroom temperature over 12 hours and was quenched with 1N HCl, thenbasified to pH 10 with 50% aqueous sodium hydroxide solution, filteredthrough celite, and extracted with ethyl acetate. The organic layer wasdried over magnesium sulfate, filtered and concentrated. The cruderesidue was purified by column chromatography (2% methanol/0.2% ammoniumhydroxide/98% dichloromethane to 5% methanol/0.5% ammonium hydroxide/95%dichloromethane) to afford the title compound (Yield: 1.9 g, 20%) whichwas used in the next step without further purification.

Step 6: Preparation of2,2-Difluoro-1S-[1-(1R-phenyl-ethyl)-pyrrolidin-3R-yl]-ethanol

To a solution of2,2-difluoro-1S-[1-(1R-phenyl-ethyl)-pyrrolidin-3R-yl]-ethanol (1.9 g,7.5 mmol) in methanol (50 mL) was added 20% Pd/C (500 mg). The reactionran under an atmosphere of hydrogen gas for 12 hours. The reactionmixture was filtered, and the filtrate concentrated to give the titlecompound (Yield: 1.1 g, quantitative). MS(APCI+): m/z 152 (M+H)+.

EXAMPLE 6 2,2,2-Trifluoro-1S-pyrrolidin-3R-yl-ethanol

Step 1: Preparation of3-(2,2,2-Trifluoro-acetyl)-1-(1R-phenyl-ethyl)-pyrrolidin-2-one

To a solution of 1-(1R-Phenyl-ethyl)-pyrrolidin-2-one (Experiment 5,step 1, 30 g, 159 mmol) in tetrahydrofuran (500 mL) at −78° C. was addedlithium diisopropylamide (97 mL of a 1.8M solution inheptane/tetrahydrofuran/ethyl benzene). The reaction stirred for 30minutes and ethyl trifluoroacetate (24.5 mL, 206 mmol) was added. After30 minutes, the reaction was quenched by the addition of saturatedaqueous ammonium chloride solution. The reaction was warmed to roomtemperature and concentrated to remove the tetrahydrofuran. The mixturewas diluted with water and extracted with ethyl acetate. The organiclayer was dried over magnesium sulfate, filtered and concentrated. Thecrude residue was purified by column chromatography (20 to 40% ethylacetate in hexanes) to afford the title compound (Yield: 33.5 g, 74%)which was used in the next step without further purification.

Step 2: Preparation of3-(2,2,2-Trifluoro-1-hydroxy-ethyl)-1-(1R-phenyl-ethyl)-pyrrolidin-2-one

To a solution of3-(2,2,2-Trifluoro-acetyl)-1-(1R-phenyl-ethyl)-pyrrolidin-2-one (5.2 g,18.2 mmol) in ether (50 mL) was added a solution of zinc borohydride(100 mmol) in ether (200 mL) via cannula. The reaction warmed to roomtemperature and stirred overnight. The reaction was quenched by thedropwise addition of saturated aqueous ammonium chloride solution. Themixture was extracted with ethyl acetate and the organic layer was driedover magnesium sulfate, filtered and concentrated. The crude residue waspurified by column chromatography (10% ether in dichloromethane) and theleast polar diastereomer was isolated as the title compound out of amixture of four diastereomers (Yield: 597 mg) which was carried into thenext step without further purification.

Step 3: Preparation of3-(2,2,2-Trifluoro-1S-hydroxy-ethyl)-1-(1R-phenyl-ethyl)-pyrrolidin-2-one

To aluminum chloride (1.0 g, 7.6 mmol) at 0° C. was addedtetrahydrofuran (10 mL) dropwise. After 5 minutes, lithium aluminumhydride (23 mL of a 1.0 M solution in tetrahydrofuran) was added. Thesolution of alane was warmed to room temperature and stirred for 20minutes, cooled to −78° C., and a solution of3-(2,2,2-Trifluoro-1-hydroxy-ethyl)-1-(1R-phenyl-ethyl)-pyrrolidin-2-one(1.88 g, 6.6 mmol) in tetrahydrofuran (10 mL) was added. The reactionwarmed to room temperature over 12 hours and was quenched with 1N HCl,then basified to pH 10 with 50% aqueous sodium hydroxide solution,filtered through celite, and extracted with ethyl acetate. The organiclayer was dried over magnesium sulfate, filtered and concentrated. Thecrude residue was purified by column chromatography (5% methanol indichloromethane) to afford the title compound (Yield: 1.6 g, 87%) whichwas used in the next step without further purification.

Step 4: Preparation of3-(2,2,2-Trifluoro-acetyl)-1-(1R-phenyl-ethyl)-pyrrolidin-2-one

To a solution of3-(2,2,2-Trifluoro-1S-hydroxy-ethyl)-1-(1R-phenyl-ethyl)-pyrrolidin-2-one(1.6 g, 5.8 mmol) in methanol (50 mL) was added 20% Pd(OH)₂/C (200 mg).The reaction ran under an atmosphere of hydrogen gas for 26 hours. Thereaction mixture was filtered, and the filtrate concentrated to give thetitle compound (Yield: 967 mg, quantitative). MS(APCI+): m/z 170 (M+H)+.

EXAMPLE 7 1-Pyrrolidin-3R-yl-ethane-1R,2-diol

Step 1: Prepaaration of 5-Hydroxymethyl-5H-furan-2-one

5-Hydroxymethyl-5H-furan-2-one was prepared according to Nagaoka,Iwashima, Abe, Yamada Tet. Lett. (1989), 30, 5911-5914.

Step 2: Preparation of 5-Triisopropylsilanyloxymethyl-5H-furan-2-one

To a solution of crude 5-Hydroxymethyl-5H-furan-2-one (3.1 g, 27 mmol)in dichloromethane (100 mL) was added imidazole (4.7 g, 69 mmol) andthen triisopropyl chloride (7.1 mL, 33 mmol) and the solution wasstirred at ambient temperature for 18 hours. The mixture wasconcentrated in vacuo, taken up in ethyl acetate (100 mL), washed withsatd. sodium bicarbonate (100 mL), satd. ammonium chloride (2×100 mL),brine (100 mL), dried with magnesium sulfate and concentrated in vacuo.The crude was run on a 100 g silica gel column eluted with 0 to 30%ethyl acetate in hexanes over 80 minutes to give 6.4 g of the titlecompound (yield: 86%). MS (APCI+): m/z 271 (M+H)+.

Step 3: Preparation of5-Triisopropylsilanyloxymethyl-4-nitromethyl-dihydro-furan-2-one

To a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (3.9 mL, 26 mmol) innitromethane (50 mL) at 0° C. was added5-Triisopropylsilanyloxymethyl-5H-furan-2-one and the solution stirredfor 30 minutes. The solution was concentrated in vacuo to approximately20 mL and diluted with ethyl acetate (225 mL) and washed with saturated.ammonium chloride (2×200 mL), brine (200 mL), dried with magnesiumsulfate and concentrated in vacuo. The crude was run on a 110 g silicagel column eluted with 0 to 25% ethyl acetate in hexanes over 2 hours togive 4.8 g of the title compound (yield: 55%). MS (APCI−): m/z 330(M−H)−.

Step 4: Preparation of4R-Aminomethyl-5S-triisopropylsilanyloxymethyl-dihydro-furan-2-one

A solution of triisopropylsilanyloxymethyl4-nitromethyl-dihydro-furan-2-one (13.9 g, 0.04 mol) in methanol (150mL) was treated with Ra—Ni (12.0 g) and hydrogenated at ˜50 psi for ˜15hours. The reaction mixture was filtered through celite (until theproduct was properly washed off the catalyst) and the filtrate wasevaporated under vacuum to give 12 g of the crude amine (yield: 98%),which is directly used in the next step. MS (APCI+): m/z 302 (M+H)+.

Step 5: Preparation of4R-(1-Hydroxy-2-triisopropylsilanyloxymethyl-ethyl)-pyrrolidin-2-one

To a solution of(5S,4R)-4-(aminomethyl)-5-{[1,1-biS(methylethyl)-2-methyl-1-silapropoxy]methyl}-4R-Aminomethyl-5S-triisopropylsilanyloxymethyl-dihydro-furan-2-one (12.0 g, 0.039 mol) in absolute ethanol (200mL) was added sodium tert-butoxide (3.81 g, 0.039 mol) at roomtemperature and after completion of addition the solution was heated to50° C. for 3 hours. The reaction mixture was cooled to room temperature,quenched with acetic acid (5 mL) and concentrated under vacuum. Theresidue was diluted with ethyl acetate (500 mL), washed with saturatedammonium chloride (1×100 mL), saturated bicarbonate (1×100 mL) and thenwith brine (1×100 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography over silica gel (50% ethyl acetate in hexane) to give 10g of the title compound (yield: 83%). MS (APCI+): m/z 302 (M+H)+.

Step 6: Preparation4R-(1S-Benzyloxy-2-triisopropylsilanyloxy-ethyl)-pyrrolidin-2-one

To a solution of benzoic acid (16.5 g, 0.135 mol) in diethyl ether (500mL) was slowly added diethylazodicarboxylate (DEAD) (23.92 g, 21.62 mL,0.137 mol) followed by a solution of triphenyl phosphine (35.5 g, 0.135mol) and4R-(1-Hydroxy-2-triisopropylsilanyloxymethyl-ethyl)-pyrrolidin-2-one(18.0 g, 0.059 mol) in diethyl ether at room temperature. The reactionmixture was stirred overnight at room temperature, the suspension (whiteprecipitate) was filtered, and the filtrate was concentrated underreduced pressure. The thick residue was purified by columnchromatography over silica gel to give 8.2 g of the title compound(yield: 34%). H¹ NMR (400 MHz, CDCl₃): δ 8.0 (d, 2H), 7.7-7.4 (m, 3H),5.2 (m, 1H), 4.2 (m, 1H), 3.9 (d, 2H), 3.6 (m, 1H), 3.4 (m, 1H), 3.2 (m,1H), 2.5 (m, 1H), 2.3 (m, 1H), 1.2-1.0 (m, 21H).

Step 7: Preparation of4R-(1S-Hydroxy-2-triisopropylsilanyloxy-ethyl)-pyrrolidin-2-one

To a solution of4R-(1S-Benzyloxy-2-triisopropylsilanyloxy-ethyl)-pyrrolidin-2-one (18.0g, 0.044 mol) in methanol (2.1 L) was added sodium methoxide (3.0 g,0.055 mol) and the solution was stirred overnight at room temperature.The solution was neutralized by Dowex 50WX8(H⁺), filtered andconcentrated under reduced pressure to give a thick residue, which uponcolumn chromatography gave 9.9 g of the title compound (yield: 74%). MS(APCI+): m/z 302 (M+H)+.Step 8: Preparation ofN-Benzyl-4R-(1S,2-dibenzyloxyethyl)-pyrrolidin-2-one

To a solution of 4R-(1S,2-dibenzyloxyethyl)-pyrrolidin-2-one (3.8 g, 13mmol) in anhydrous tetrahydrofuran (100 mL) at 0° C. was added 1.0 Mtetrabutylammonium fluoride in tetrahydrofuran (15 mL, 15 mmol). Thesolution was allowed to come to ambient temperature and stirred for 2hours. To the solution was added benzyl bromide (9 mL, 76 mmol) andtetrabutylammonium iodide (0.94 g, 3 mmol) and the solution was cooledto 0° C. To the solution was slowly added 60 wt % sodium hydride in oil(3.6 g, 90 mmol). The ice bath was removed and the mixture stirred for15 minutes. The mixture was then heated at 60° C. for 2.5 hours. Thesolution was concentrated in vacuo and taken up in ethyl acetate (200mL), washed with saturated. ammonium chloride (200 mL), saturated sodiumbicarbonate (200 mL), brine (200 mL), dried with magnesium sulfate andconcentrated in vacuo. The crude product was purified on a 120 g silicagel column eluted with 10 to 100% ethyl acetate in hexanes over 1 hourto give 3.5 g of the title compound (yield: 66%). MS (APCI+): m/z 416(M+H)+.

Step 9: Preparation of N-Benzyl-4R-(1S,2-dibenzyloxyethyl)-pyrrolidine

To a solution of N-Benzyl-4R-(1S,2-dibenzyloxyethyl)-pyrrolidin-2-one(3.5 g, 8 mmol) in tetrahydrofuran (80 mL) at 0° C. was slowly added 1.0M solution of lithium aluminum hydride in tetrahydrofuran (17 mL, 17mmol). The solution was heated at 70° C. for 1.5 hours. The solution wascooled to 0° C. and water (0.65 mL), 15% sodium hydroxide solution inwater (0.65 mL) and water (2 mL) were added carefully. The mixture wasstirred at ambient temperature for 1 hour and then filtered through apad of celite and rinsed with tetrahydrofuran (50 mL). The filtrate wasconcentrated in vacuo to give 3.2 g of the title compound (yield: 95%).MS (APCI+): m/z 402 (M+H)+.

Step 10: Preparation of 1-Pyrrolidin-3R-yl-ethane-1R,2-diol

A mixture of N-Benzyl-4R-(1S,2-dibenzyloxyethyl)-pyrrolidine (3.3 g, 8mmol) and 20 wt % palladium hydroxide on carbon (1.2 g) in methanol (100mL) was hydrogenated. The catalyst was removed by filtration and thefiltrate was concentrated in vacuo to give 1.1 g of the title compound(yield: 100%). MS (APCI+): m/z 132 (M+H)+.

EXAMPLE 8 Pyrrolidin-3-yl-thiazol-2-yl-methanol

Step 1: Preparation of N-Benzyloxycarbonyl Pyrrolidine-3-carboxylic AcidEthyl Ester

To a solution of N-Benzyl Pyrrolidine-3-carboxylic acid ethyl ester (4.0g, 17.14 mmol) in chloroform (40 mL) was added benzyl chloroformate(4.94 mL, 34.6 mmol). The mixture was heated at reflux for 4 hours.After evaporation of the solvent, the residue was purified by columnchromatography on silica gel (1:2 ethyl acetate:hexanes to give thetitle compound (Yield: 4.0 g, 85%). ¹H NMR (200 MHz, CDCl₃) δ 7.43-7.28(m, 5H), 5.12 (s, 2H), 4.244.08 (dd, 2H), 3.75-3.35 (m, 4H), 3.15-2.95(m, 1H), 2.22-2.06 (m, 2H), 1.32-1.20 (t, 3H).

Step 2: Preparation of N-Benzyloxycarbonyl-Pyrrolidin-3-yl-methanol

To a solution of N-Benzyloxycarbonyl Pyrrolidine-3-carboxylic acid ethylester (1.0 g, 3.6 mmol) in tetrahydrofuran (100 mL) was slowly addedsodium borohydride (0.2 g, 5.4 mmol), followed by the slow addition ofmethanol (2 mL) under ice-water cooling. The mixture was stirred at roomtemperature for 2 hours. Solvent was evaporated and the residue wasdissolved in ethyl acetate (100 mL), washed with water (100 mL) andbrine (100 mL), and dried over Na₂SO₄. Evaporation of the solvent gavethe title compound (Yield: 0.56 g, 56%). ¹H NMR (200 MHz, CDCl₃) δ7.42-7.30 (m, 5H), 5.13 (s, 2H), 3.68-3.32 (m, 5H), 3.28-3.10 (m, 1H),2.52-2.32 (m, 1H), 2.10-1.90 (m, 1H), 1.80-1.50 (m, 2H).

Step 3: Preparation of N-Benzyloxycarbonyl Pyrrolidine-3-carbaldehyde

To a solution of oxalyl chloride (0.23 mL, 2.8 mmol) in dichloromethane(5 mL) at −75° C. was added dimethylsulfoxide (0.43 mL, 5.6 mmol)dissolved in dichloromethane (1 mL) and the solution stirred for 2minutes. N-Benzyloxycarbonyl-Pyrrolidin-3-yl-methanol (0.56 g, 2.5 mmol)in dichloromethane (2 mL) was slowly added and stirred at the sametemperature for 0.5 h. Triethylamine (1.8 mL, 12.8 mmol) was then added.The solution was stirred at the same temperature for 5 minutes and letwarm to room temperature. Water (10 mL) was added and the products wereextracted with dichloromethane (100 mL). The organic extract was washedwith water (1×100 mL) and brine (1×100 mL), and dried over Na₂SO₄. Afterevaporation of the solvent the residue was purified by columnchromatography on silica gel (1:1 ethyl acetate:hexanes) to obtain thetitle compound (Yield: 0.46 g, 78%). ¹H NMR (200 MHz, CDCl₃) δ 9.70 (s,1H), 7.42-7.28 (m, 5H), 5.14 (s, 2H), 3.90-3.72 (m, 1H), 3.68-3.35 (m,3H), 3.15-2.96 (m, 1H), 2.32-2.02 (m, 2H).

Step 4: Preparation of N-BenzyloxycarbonylPyrrolidin-3-yl-thiazol-2-yl-methanol

To a stirred solution of 2-bromothiazole (0.90 g, 5.5 mmol) in anhydrousdiethyl ether (10 mL), cooled to −70° C. was added a solution ofn-butyllithium (2.0 mL of 2.5 M solution in hexane, 5.0 mmol) undernitrogen by syringe and stirring was continued for 30 minutes at −70° C.A solution of N-benzyloxycarbonyl pyrrolidine-3-carbaldehyde (1.17 g,5.0 mmol) in anhydrous tetrahydrofuran (2 mL) was added by syringe at−70° C., the mixture was stirred at −70° C. for 1 hour, and then it wasallowed to warm to 0° C. The mixture was quenched with saturated aqueousNH₄Cl solution and extracted with ethyl acetate. The organic layer wasseparated, washed with saturated aqueous NH₄Cl solution, brine, driedover anhydrous Na₂SO₄ and concentrated under vacuum. Purification byflash chromatography over silica gel (hexane/ethyl acetate, 3:2 to 1:2)gave the title compound as pale yellow oil (Yield: 0.66 g, 42%). ¹H NMR(400 MHz, CDCl₃) δ 7.71 (m, 1H), 7.38-7.24 (m, 6H), 5.10 (m, 2H),4.98-4.87 (m, 1H), 4.07-3.90 (m, 1H), 3.64-3.28 (m, 4H), 2.72 (m, 1H),1.98-1.77 (m, 2H).

Step 5: Preparation of Pyrrolidin-3-yl-thiazol-2-yl-methanol

To a stirred solution of N-BenzyloxycarbonylPyrrolidin-3-yl-thiazol-2-yl-methanol (0.66 g, 2.0 mmol) in anhydrousdichloromethane (15 mL) cooled to 0° C. was added neat trimethylsilyliodide (0.60 g, 3.0 mmol) under nitrogen by syringe and stirring wascontinued for 30 minutes at 0° C. An aqueous 2 N HCl solution (3 mL) wasadded followed by hexane (15 mL), and the mixture was concentrated undervacuum at room temperature. The residue was washed with diethyl etherand the ether extracts were discarded. The aqueous phase wasconcentrated under vacuum to dryness, dissolved in methanol (30 mL) andstirred with the basic form of Amberlite IRA-400 (1.5 g) for 30 minutesat room temperature. The solution was filtered through celite andconcentrated under vacuum to give the title compound as pale yellow oil(Yield: 0.33 g, 89%). ¹H NMR (400 MHz, CDCl₃) δ 7.66 (m, 1H), 7.27 (m,1H), 5.01 and 4.89 (d each, 1H), 3.35-2.90 (m, 7H), 2.86-2.70 (m, 1H),2.04-1.78 (m, 2H).

EXAMPLE 9 2,2-Difluoro-2-pyrrolidin-3-yl-ethanol

Step 1: Preparation of1-Benzyl-3-(2-benzyloxy-1,1-difluoro-ethyl)-pyrrolidine

2-Benzyloxy-1-(1-benzyl-pyrrolidin-3-yl)-ethanone (prepared as indicatedin Example 1, 587 mg, 1.90 mmol) was dissolved in dichloromethane (1.5ml) under nitrogen and cooled to 0° C. Diethylaminosulfur trifluoridewas added dropwise over 5 minutes and the reaction was heated at 60° C.for four hours. The reaction was poured onto an ice/water mixture (100ml) and extracted with dichloromethane (3×30 ml). The solvent wasremoved under reduced pressure and the residue was purified on silicagel by flash chromatography (0-5% isopropanol in dichloromethane) toyield 166 mg (26%) of the title compound. LCMS: m/z 332.3 (M+1).

Step 2: Preparation of 2,2-Difluoro-2-pyrrolidin-3-yl-ethanol

To a solution of 1-Benzyl-3-(2-benzyloxy-1,1-difluoro-ethyl)-pyrrolidine(166 mg, 0.50 mmol) in methanol was added 20% Pd/C. The reaction wasconducted under an atmosphere of hydrogen gas for 12 hours. The mixturewas filtered and the filtrate was concentrated to give the titlecompound (74 mg, 98%). LCMS: m/z 153.4 (M+1).

EXAMPLE 10 (1-Hydroxymethyl-cyclopropyl)-pyrrolidin-3-yl-methanolAcetate Salt

Step 1: Preparation of1-[(1-Benzyl-2-oxo-pyrrolidin-3-ylidene)-hydroxy-methyl]-cyclopropanecarboxylicAcid Ethyl Ester

LDA (1M, 13 mL) was stirred in THF (25 mL) at −78° C., then1-benzyl-pyrrolidine (2.0 g, in solution of THF, 3 mL) was added. Afterstirring for 30 minutes, cyclopropane-1,1-dicarboxylic acid diethylester (2.80 g, in solution of THF, 3 mL) was added. The reaction wasstirred at −78° C. for another 15 minutes, then at 0° C. for 1 hour. Thereaction mixture was quenched with saturated NH₄Cl, diluted with EtOAc,then washed with water and brine. The organic layer was dried overMgSO₄, filtered and the filtrate was concentrated at reduced pressure.The resulting residue was purified via flash column chromatography(Hexanes/EtOAc gradient) to afford the title compound (2.0 g, 55%). MS(APCI+): m/z 316 (M+H)+.

Step 2: Preparation of(1-Benzyl-pyrrolidin-3-yl)-(1-hydroxymethyl-cyclopropyl)-methanol

AlCl₃ (0.89 g) was cooled to 0° C., then THF (10 mL) was added slowly.After 15 minutes, LAH (1M, 18 mL) was added slowly over 5 minutes. Thereaction mixuture was stirred at 0° C. for 15 minutes, warmed to roomtemperature for 30 minutes, then cooled to −78° C. Preparation of1-[(1-Benzyl-2-oxo-pyrrolidin-3-ylidene)hydroxy-methyl]-cyclopropanecarboxylicacid ethyl ester (2.10 g, in THF solution, 5 mL) was added. The reactionmixture was stirred at −78° C. for 15 minutes, then warmed to roomtemperature for 1 hour. 1.0 N HCl was added until bubbling ceased. Thereaction mixture was diluted with EtOAc, washed with saturated Na₂CO₃,water, and brine. The organic layer was dried over MgSO₄, filtered andthe filtrate was concentrated at reduced pressure to afford the titlecompound (1.75 g, 100%). MS (APCI+): m/z 262 (M+H)+.

Step 3: Preparation of(1-Hydroxymethyl-cyclopropyl)-pyrrolidin-3-yl-methanol Acetate Salt

To a solution of(1-Benzyl-pyrrolidin-3-yl)-(1-hydroxymethyl-cyclopropyl)-methanol (1.70g) in methanol (20 mL) was added 20% Pd/C (0.20 g) and HOAc (0.5 mL).The reaction mixture was hydrogenated for over 20 hours, then thecatalyst was filtered, and filtrate concentrated to afford the titlecompound (1.75 g, 100%). MS (APCI+): m/z 172+(M+H)+.

EXAMPLE 11 (5-Methanesulfonyl-furan-2-yl)-pyrrolidin-3-yl-methanol

Step 1: Preparation of 5-Nitro-furan-2-carboxylic Acid Ethyl Ester

5-Nitro-furan-2-carboxylic acid was stirred in dichloromethane (50 mL),then oxalyl chloride (2.60 g) and DMF (1 mL) were added. After 45minutes, the reaction mixture was concentrated, and the resultingresidue was stirred in CH₂Cl₂ (50 mL) at 0° C. After the solution wassufficiently cooled, EtOH (4 mL) and triethylamine (4.40 mL) were added.After 15 minutes, the reaction mixture was warmed to room temperatureand was allowed to stir for 1 hour. The reaction mixture was then washedwith saturated NaHCO₃, water, and brine. The organic layer was driedover MgSO₄, filtered and the filtrate was concentrated at reducedpressure to afford the title compound (2.89 g, 98%). ¹H NMR (400 MHz,CDCl₃): 7.33 (1H, d, J=3.9 Hz), 7.26 (1H, d, J=6.8 Hz), 4.44 (2H, t,J=7.1 Hz), 1.41 (3H, q, J=7.1 Hz).

Step 2: Preparation of 5-Methylsulfanyl-furan-2-carboxylic Acid EthylEster

To a solution of 5-Nitro-furan-2-carboxylic acid ethyl ester (2.90 g) inDMSO (20 mL) was added NaSMe (1.20 g). The resulting reaction mixturewas heated overnight to 100° C., then quenched with saturated NH₄Cl. Themixture was diluted with EtOAc and washed with saturated NaHCO₃, water,and brine. The organic layer was dried over MgSO₄, filtered and thefiltrate was concentrated to at reduced pressure to afford the titlecompound (2.70 g, 92%). ¹H NMR (400 MHz, CDCl₃): 7.13 (1H, d, J=3.7 Hz),6.36 (1H, d, J=3.7 Hz), 4.34 (2H, t, J=7.1 Hz), 2.50 (3H, s), 1.36 (3H,q, J=7.1 Hz).

Step 3: Preparation of 5-Methanesulfonyl-furan-2-carboxylic Acid EthylEster

To a solution of 5-Methylsulfanyl-furan-2-carboxylic acid ethyl ester(5.30 g) in CH₂Cl₂ (50 mL) was added mCPBA (10.0 g). The resultingreaction mixture was heated to reflux. After 4 hours, the reactionmixture was washed with saturated Na₂CO₃, H₂O, and brine. The organiclayer was dried over MgSO₄, filtered and the filtrate was concentratedat reduced pressure to afford the title compound (3.96 g, 64%). ¹H NMR(400 MHz, CDCl₃): 7.22-7.19 (1H, m), 5.29 (1H, s), 4.39 (2H, t, J=7.1Hz), 3.21 (3H, s), 1.39 (3H, q, J=7.1 Hz).

Step 4: Preparation of1-Benzyl-3-[hydroxy-(5-methanesulfonyl-furan-2-yl)-methylene]-pyrrolidin-2-one

LDA was stirred in THF (50 mL) at −78° C., then 1-benzyl-2-pyrrolidinone(in solution of THF, 5 mL) was added dropwise over 2 minutes. After 45minutes, 5-Methanesulfonyl-furan-2-carboxylic acid ethyl ester (insolution of THF, 3 mL) was added dropwise over 5 minutes. Afteradditional 15 minutes at −78° C., reaction was warmed to roomtemperature. After 90 minutes, the reaction mixture was diluted withEtOAc and washed with saturated NH₄C₁, H₂O, and brine. Organic layer wasdried over MgSO₄, filtered and filtrate concentrated. Resulting residuewas purified via flash column chromatography (Hexanes/EtOAc gradient) toafford the title compound (5.02 g, 87%). MS (APCI+): m/z 348 (M+H)+.

Step 5: Preparation of1-Benzyl-3-[hydroxy-(5-methanesulfonyl-furan-2-yl)-methyl]-pyrrolidin-2-one

To a solution of1-Benzyl-3-[hydroxy-(5-methanesulfonyl-furan-2-yl)-methylene]-pyrrolidin-2-one(5.02 g) in MeOH (20 mL) and THF (20 mL) was added sodium borohydride(NaBH₄) (1.65 g) portionwise. After 16 hours, the reaction mixture wasconcentrated. The resulting residue was dissolved in EtOAc, and theresulting solution was washed with water and brine. The organic layerwas dried over MgSO₄, filtered, and the filtrate was concentrated atreduced pressure to afford the title compound (3.99 g, 79%). MS (APCI+):m/z 350 (M+H)+.

Step 6: Preparation of(1-Benzyl-pyrrolidin-3-yl)-(5-methanesulfonyl-furan-2-yl)-methanol

AlCl₃ (1.34 g) was cooled to 0° C., then THF (10 mL) was added slowly.After 15 minutes, LAH (1M, 30 mL) was added slowly over 5 minutes. Thereaction mixture was stirred at 0° C. for 15 minutes, warmed to roomtemperature for 30 minutes, then cooled to −78° C.1-Benzyl-3-[hydroxy-(5-methanesulfonyl-furan-2-yl)-methyl]-pyrrolidin-2-one(3.50 g, in THF solution, 5 mL) was then added. The reaction mixture wasstirred at −78° C. for 15 minutes, then warmed to room temperature for 1hour. 1N HCl was added until bubbling ceased. The reaction mixture wasdiluted with EtOAc, washed with saturated Na₂CO₃, H₂O, and brine. Theorganic layer was dried over MgSO₄, filtered and the filtrate wasconcentrated at reduced pressure to afford the title compound (3.02 g,90%). MS (APCI+): m/z 336 (M+H)+.

Step 7: Preparation of1-Benzyl-3-[(5-methanesulfonyl-furan-2-yl)-methoxymethoxy-methyl]-pyrrolidine

To a solution of(1-Benzyl-pyrrolidin-3-yl)-(5-methanesulfonyl-furan-2-yl)-methanol (2.80g) in THF (20 mL) at 0° C. was added NaH in small portions. After 15minutes, the reaction mixture was warmed to room temperature for 30minutes. Not all the solid was soluble, so the reaction mixture was thenheated to reflux for 14 minutes, then cooled to room temperature.Methoxymethyl chloride (MOMCl) (0.74 g) was then added. After 2 hours,the reaction mixture was diluted with EtOAc and washed with saturatedNH₄Cl, H₂O, and brine. The organic layer was dried over MgSO₄, filteredand the filtrate was concentrated at reduced pressure. The resultingresidue was purified via flash column chromatography (Hexanes/EtOAcgradient) to afford the title compound (0.98 g, 34%). MS (APCI+): m/z380 (M+H)+.

Step 8: Preparation of(5-Methanesulfonyl-furan-2-yl)-pyrrolidin-3-yl-methanol

To a solution of1-Benzyl-3-[(5-methanesulfonyl-furan-2-yl)-methoxymethoxy-methyl]-pyrrolidine(0.97 g) in CH₂Cl₂ (10 mL) at 0° C. was added 1-chloroethylchloroformate (0.44 g). After 15 minutes, the reaction mixture waswarmed to room temperature for 30 minutes. The reaction mixture was thenconcentrated and the resulting residue was dissolved in MeOH (20 mL) andheated to reflux. After 3 hours, the reaction mixture was cooled to roomtemperature and concentrated HCl (0.5 mL) was added. The reactionmixture was heated to reflux for another 4 hours, then concentrated. Theresulting residue was dissolved in EtOAc and washed with saturatedNaHCO₃ and H₂O. The aqueous layers were combined and concentrated. Theresulting solids were stirred in MeOH/CH₂Cl₂, filtered and the filtrateconcentrated at reduced pressure to afford the title compound as an HClsalt (0.29 g, 46%). MS (APCI+): m/z 246 (M+H)°.

EXAMPLE 123-{(tert-Butyl-dimethyl-silanyloxy)-[1-(tert-butyl-dimethyl-silanyloxy)-cyclopropyl]-methyl}-pyrrolidine

Step 1: Preparation of1-(tert-Butyl-dimethyl-silanyloxy)-cyclopropanecarboxylic Acid EthylEster

To a solution of 1-Hydroxy-cyclopropanecarboxylic acid ethyl ester (3.0g) and 2,6-lutidine (2.72 g) in dichloromethane (20 mL) at 0° C. wasadded tert butyldimethyl silyltrifluoromethanesulfonate (6.09 g). After15 minutes at 0° C., the reaction mixture was warmed to roomtemperature. After 30 minutes, the reaction mixture was concentrated toafford crude 1-(tert-Butyl-dimethyl-silanyloxy)-cyclopropanecarboxylicacid ethyl ester, which was used immediately without purification.

Step 2: Preparation of1-Benzyl-3-{[1-(tert-butyl-dimethyl-silanyloxy)-cyclopropyl]-hydroxy-methylene}-pyrrolidin-2-one

LDA (2M, 14 mL) was stirred in THF (50 mL) at −78° C., then1-benzyl-2-pyrrolidinone (4.04 g) was added slowly as solution in THF (5mL). After 30 minutes, crude1-(tert-Butyl-dimethyl-silanyloxy)-cyclopropanecarboxylic acid ethylester was added as a solution in THF (5 mL). The reaction mixtureremained at −78° C. for 30 minutes, and then was warmed to 0° C. After 1hour, saturated NH₄Cl was added to quench excess base, then the reactionmixture was diluted with EtOAc and washed with saturated NaHCO₃, water,and brine. The organic layer was dried over MgSO₄, filtered, and thefiltrate was concentrated. The resulting residue was purified via flashcolumn chromatography (Hexanes/EtOAc gradient) to afford the titlecompound (3.23 g, 38%). MS (APCI+): m/z 374 (M+H)+.

Step 3: Preparation of1-Benzyl-3-{[1-(tert-butyl-dimethyl-silanyloxy)-cyclopropyl]-hydroxy-methylene}-pyrrolidine

AlCl₃ (1.40 g) was cooled to 0° C., then THF (10 mL) was added slowly.After 15 minutes, LAH (1M, 31 mL) was added slowly over 5 minutes. Thereaction mixture was stirred at 0° C. for 15 minutes, warmed to roomtemperature for 30 minutes, then cooled to −78° C.1-Benzyl-3-{[1-(tert-butyl-dimethyl-silanyloxy)-cyclopropyl]-hydroxy-methylene}-pyrrolidin-2-one(3.23 g, in THF solution, 5 mL) was added. The reaction was stirred at−78° C. for 15 minutes, then warmed to room temperature for 1 hour. 1NHCl was added until bubbling ceased. Reaction mixture was diluted withEtOAc, washed with saturated Na₂CO₃, H₂O, and brine. The organic layerwas dried over MgSO₄, filtered and the filtrate was concentrated atreduced pressure to afford the title compound (3.20 g, 100%). MS(APCI+): m/z 362 (M+H)+.

Step 4: Preparation of1-Benzyl-3-{[1-(tert-butyl-dimethyl-silanyloxy)-cyclopropyl]-(tert-butyl-dimethyl-silanyloxy)-methylene}-pyrrolidine

To a solution of1-Benzyl-3-{[1-(tert-butyl-dimethyl-silanyloxy)-cyclopropyl]-hydroxy-methylene}-pyrrolidine(3.20 g) and 2,6-lutidine (0.95 g) in CH₂Cl₂ (20 mL) was addedtert-butyldimethylsilyltrifluoromethanesulfonate (6.09 g). The reactionwas stirred at 0° C. for 15 minutes, then warmed to room temperature.After 30 minutes, the reaction mixture was concentrated. Purificationvia flash column chromatography (Hexanes/EtOAc gradient) afforded thetitle compound (0.87 g, 21%). MS (APCI+): m/z 476 (M+H)+.

Step 5: Preparation of3-{[1-(tert-butyl-dimethyl-silanyloxy)-cyclopropyl]-(tert-butyl-dimethyl-silanyloxy)-methylene}-pyrrolidine

To a solution of1-Benzyl-3-{[1-(tert-butyl-dimethyl-silanyloxy)-cyclopropyl]-(tert-butyl-dimethyl-silanyloxy)-methylene}-pyrrolidine(0.87 g) in CH₂Cl₂ (20 mL) at 0° C. was added 1-chloroethylchloroformate (0.39 g). After 15 minutes, the reaction was warmed toroom temp for 1 hour. The reaction mixture was concentrated and theresulting residue was dissolved in methanol (10 mL) and heated toreflux. After 3 hours, the reaction mixture was cooled to roomtemperature and concentrated to afford the title compound as the HClsalt (0.78 g, 100%). MS (APCI+): m/z 386 (M+H)+.

EXAMPLE 13 Preparation of Octahydro-cyclopenta[c]pyrrol-4-ol Step 1:Preparation of 2-Benzyl-hexahydro-cyclopenta[c]pyrrol-4-one

To a solution of 2-cyclopenten-1-one (10.2 mL, 122 mmol) andbenzyl-1-methoxymethyl-1-trimethylsilylmethyl amine (34.8 g, 146 mmol)in dichloromethane (240 mL) was added trifluoroacetic acid (11 mL, 1 Min dichloromethane). The reaction mixture was allowed to warm to roomtemperature over 18 hours. The mixture was diluted with saturatedaqueous sodium bicarbonate, and the organic phase was removed. Theaqueous layer was extracted two times with dichloromethane, and thecombined organic layers were washed with saturated aqueous sodiumbicarbonate, dried over magnesium sulfate, filtered, and concentrated invacuo to provide the title compound (26.3 g, 100%) as a dark orangeliquid which was used without further purification. MS(APCI+): m/z 216.1(M+H)⁺.

Step 2: 4-Oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic Acid BenzylEster

To a solution of 2-benzyl-hexahydro-cyclopenta[c]pyrrol-4-one (26.3 g,122 mmol) in dichloromethane (1000 mL) was added benzyl chloroformate(30.0 mL, 207 mmol). The reaction mixture was allowed to stir at roomtemperature for 24 hours and was then concentrated in vacuo. Theresulting residue was purified on a 65M Biotage column using an ethylacetate/hexanes gradient to afford the title compound (16.0 g, 51%) as ayellow liquid. MS(APCI+): m/z 260.2 (M+H)⁺, 216.2 (M−CO₂+H)⁺.

Step 3: Preparation of4-Hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic Acid Benzyl Ester

To a cooled (−78° C.) solution of4-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (7.5g, 29 mmol) in tetrahydrofuran (70 mL) was added lithiumtri-sec-butylborohydride (43 mL, 43 mmol, 1 M in tetrahydrofuran)dropwise by addition funnel. The reaction mixture was allowed to slowlywarm to room temperature over 18 hours. The mixture was cooled to 0° C.and 30% hydrogen peroxide was added dropwise with caution until all gasevolution ceased. The quenched solution was poured into water andextracted three times with ethyl acetate. The combined organics werewashed with brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was purified on a 40L Biotage columnusing an ethyl acetate/dichloromethane gradient to afford the titlecompound (6.8 g, 90%) as a yellow oil. MS(APCI+): m/z 262.2 (M+H)⁺,218.2 (M−CO₂+H)⁺.

Step 4: Preparation of Octahydro-cyclopenta[c]pyrrol-4-ol

To a solution of 4-Hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylicacid benzyl ester (2.5 g, 9.6 mmol) in tetrahydrofuran (50 mL) in a Parrshaker was added 10% palladium on carbon (1.5 g), and hydrogen gas wasintroduced at 40 psi for 40 hours. The reaction mixture was diluted withmethanol, filtered through diatomaceous earth (Celite®), andconcentrated in vacuo to afford the title compound (1.2 g, 99%) as ayellow solid which was used without further purification. MS(APCI+): m/z128.0 (M+H)⁺.

EXAMPLE 14 Preparation of Octahydro-cyclopenta[c]pyrrol-4-ol Step 1:Preparation of 4-Benzoyloxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylicAcid Benzyl Ester

To a solution of 4-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylicacid benzyl ester (4.3 g, 16 mmol) in tetrahydrofuran (50 mL) was addedtriphenylphosphine (5.6 g, 21 mmol), benzoic acid (2.6 g, 21 mmol), anddiisopropyl azodicarboxylate (DIAD) (4.2 mL, 21 mmol), in that order.The resulting yellow solution was stirred at room temperature for 20hours and concentrated in vacuo. The residue was purified on a 40LBiotage column using an ethyl acetate/hexanes gradient to afford thetitle compound (4.8 g, 80%) as a colorless oil. MS(APCI+): m/z 366.1(M+H)⁺, 322.1 (M−CO₂+H)⁺.

Step 2: Preparation of4-Hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic Acid Benzyl Ester

To a solution of4-benzoyloxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzylester (4.8 g, 13 mmol) in methanol (65 mL) was added sodium methoxide(1.4 g, 26 mmol), and the reaction mixture was stirred at roomtemperature for 4 hours and concentrated in vacuo. The resulting whiteresidue was partitioned between saturated aqueous ammonium chloride anddichloromethane. The aqueous phase was extracted two times withdichloromethane, and the combined organics were dried over magnesiumsulfate, filtered, and concentrated in vacuo. The residue was purifiedon a 40M Biotage column using and ethyl acetate/dichloromethane gradientto afford the title compound (2.5 g, 73%) as a colorless oil. MS(APCI+):m/z 262.2 (M+H)⁺, 218.2 (M−CO₂+H)⁺.

Step 3: Preparation of Octahydro-cyclopenta[c]pyrrol-4-ol

To a solution of 4-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylicacid benzyl ester (2.5 g, 9.6 mmol) in tetrahydrofuran (50 mL) andmethanol (50 mL) in a Parr shaker was added 20% palladium on carbon(0.40 g), and hydrogen gas was introduced at 40 psi for 15 hours. Thereaction mixture was diluted with methanol, filtered throughdiatomaceous earth (Celite®), and concentrated in vacuo to afford thetitle compound (1.2 g, 99%) as a yellow solid which was used withoutfurther purification. MS(APCI+): m/z 128.0 (M+H)⁺.

EXAMPLE 15 Preparation of Octahydro-cyclopenta[c]pyrrole-4,5-diol Step1: Preparation of3,3a,4,6a-Tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylic Acid BenzylEster

To a solution of 4-Hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylicacid benzyl ester (1.5 g, 5.7 mmol) in toluene (60 mL) was added(methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (1.8 g,7.5 mmol). The reaction mixture was heated at 120° C. for 24 hours,concentrated in vacuo, and partitioned between ethyl acetate andsaturated aqueous sodium bicarbonate. The aqueous phase was extractedtwo times with ethyl acetate, and the combined organics were washed withbrine, dried over magnesium sulfate, filtered, and concentrated invacuo. The residue was purified on a 40S Biotage column using an ethylacetate/hexanes gradient to afford the title compound (0.38 g, 27%) as acolorless oil. MS(APCI+): m/z 244.2 (M+H)⁺, 200.1 (M-CO₂+H)⁺.

Step 2: Preparation of4,5-Dihydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic Acid BenzylEster

To a solution of3,3a,4,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid benzylester (0.53 g, 2.2 mmol) in acetone (6 mL), tert-butyl alcohol (1.3 mL),and water (6 mL) was added 4-methylmorpholine N-oxide (0.38 g, 3.2 mmol)followed by osmium tetroxide (0.13 mL, 0.011 mmol, 2.5 wt % in2-methyl-2-propanol). The resulting yellow reaction mixture was stirredat room temperature for 3 hours and diluted with saturated aqueoussodium bisulfite and ethyl acetate. The aqueous phase was extractedthree times with ethyl acetate, and the combined organics were washedwith brine, dried over magnesium sulfate, filtered, and concentrated invacuo. The residue was purified on a 10 g Isco column using amethanol/dichloromethane gradient to afford the title compound as aracemic mixture of syn diols (0.54 g, 90%). MS(APCI+): m/z 278.2 (M+H)⁺,234.2 (M−CO₂+H)⁺.

Step 3: Preparation of Octahydro-cyclopenta[c]pyrrole-4,5-diol

To a solution of4,5-dihydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzylester (0.54 g, 1.9 mmol) in methanol (50 mL) in a Parr shaker was added20% palladium hydroxide on carbon (0.050 g), and hydrogen gas wasintroduced at 37 psi for 28 hours. The reaction mixture was diluted withmethanol, filtered through diatomaceous earth (Celite®), andconcentrated in vacuo to afford the title compound (0.28 g, 100%) whichwas used without further purification. MS(APCI+): m/z 144.1 (M+H)⁺.

EXAMPLE 16 Preparation of4-Hydroxymethyl-octahydro-cyclopenta[c]pyrrol-4-ol Step 1:4-Benzyloxymethyl-4-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylicAcid Benzyl Ester

To a solution of 4-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acidbenzyl ester (1.5 g, 5.8 mmol) in tetrahydrofuran (60 mL) was addedbenzyl chloromethyl ether (1.6 mL, 12 mmol, 60% technical grade)followed by samarium iodide (6.34 g, 15.7 mmol). The dark blue reactionmixture was stirred at room temperature for 3.5 hours, during which timeit turned bright yellow. The mixture was diluted with saturated aqueousammonium chloride and ethyl acetate. The aqueous layer was extracted twotimes with ethyl acetate, and the combined organics were washed withbrine, dried over magnesium sulfate, filtered, and concentrated invacuo. The residue was purified on a 40L Biotage column (0:100 to 80:20ethyl acetate/hexanes) to afford the title compound (0.66 g, 30%) as acolorless oil. MS(APCI+): m/z 382.4 (M+H)⁺, 338.2 (M-CO₂+H)⁺.

Step 2: Preparation of 4-Hydroxymethyl-octahydro-cyclopenta[c]pyrrol-4-ol

To a solution of4-benzyloxymethyl-4-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylicacid benzyl ester (1.15 g, 3.01 mmol) in ethanol (50 mL) in a Parrshaker was added 20% palladium on carbon (1.0 g), and hydrogen gas wasintroduced at 37 psi for 100 hours. The reaction mixture was dilutedwith methanol, filtered through diatomaceous earth (Celite®), andconcentrated in vacuo to afford the title compound (0.43 g, 91%) whichwas used without further purification. MS(APCI+): m/z 158.1 (M+H)⁺.

EXAMPLE 17 Preparation of Preparation of5-Fluoro-octahydro-cyclopenta[c]pyrrol-4-ol Isomers Step 1: Preparationof6-(tert-Butyl-dimethyl-silanyloxy)-3,3a,4,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylicacid benzyl ester

To a cooled (0° C.) solution of4-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl esterproduct (5.2 g, 20 mmol) and 2,6-lutidine (4.6 mL, 40 mmol) indichloromethane (150 mL) was added tert-butyldimethylsilyltrifluoromethanesulfonate (7.0 mL, 30 mmol). The reaction mixture waswarmed to room temperature and after 20 hours, the mixture was dilutedwith saturated aqueous sodium bicarbonate and dichloromethane. Theaqueous phase was extracted two times with dichloromethane, and thecombined organics were dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was purified on a 40M Biotage columnusing an ethyl acetate/hexanes gradient to afford the title compound(6.9 g, 92%). MS(APCI+): m/z 374.1 (M+H)⁺.

Step 2: Preparation of5-Fluoro-4-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic Acid BenzylEster (A) and 5-Fluoro-4-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylicAcid Benzyl Ester (B)

To a solution of example 23 product (16.2 g, 43.4 mmol) in acetonitrile(400 mL) was added Selectfluor™ (20.0 g, 56.4 mmol). After 2.5 hours,the solvent was removed in vacuo, and the resulting residue waspartitioned between water and dichloromethane. The aqueous phase wasextracted two times with dichloromethane, and the combined organics werewashed with brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was purified on a 40L Biotage columnusing an ethyl acetate/hexanes solvent system to afford the titlecompounds (A, 6.2 g, 52%; B, 1.6 g, 13%). MS(APCI+): m/z 278.1 (M+H)⁺.

Step 3A: Preparation of 5-Fluoro-4-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic Acid Benzyl Ester (A)

To a cooled (−78° C.) solution of5-Fluoro-4-oxo-hexahydro-cyclopenta[c]pyrrole-2arboxylic acid benzylester (A) (1.8 g, 6.5 mmol) in tetrahydrofuran (30 mL) was added lithiumtri-sec-butylborohydride (7.8 mL, 7.8 mmol, 1 M in tetrahydrofuran)dropwise. After 45 minutes, the reaction mixture was warmed to roomtemperature, then cooled to 0° C., and 30% aqueous H₂O₂ was addeddropwise with caution until all gas evolution ceased. The mixture waswarmed to room temperature, poured into water, and extracted three timeswith ethyl acetate. The combined organics were washed with brine, driedover magnesium sulfate, filtered, and concentrated in vacuo to give thetitle compound (1.8 g, 100%) which was used without furtherpurification. MS(APCI+): m/z 280.2 (M+H)⁺, 236.2 (M-CO₂+H)⁺.

Step 4A: Preparation of 5-Fluoro-octahydro-cyclopenta[c]pyrrol-4-ol

To a solution of5-Fluoro-4-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acidbenzyl ester (A) (0.46 g, 1.6 mmol) in tetrahydrofuran (50 mL) in a Parrshaker was added 20% palladium on carbon (0.19 g), and hydrogen gas wasintroduced at 37 psi for 15 hours. The reaction mixture was diluted withmethanol, filtered through diatomaceous earth (Celite®), andconcentrated in vacuo to afford the title compound (0.24 g, 100%) whichwas used without further purification. MS(APCI+): m/z 146.1 (M+H)⁺.

Step 3B: Preparation of 5-Fluoro-4-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic Acid Benzyl Ester (B)

To a cooled (−78° C.) solution of5-Fluoro-4-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzylester (B) (2.0 g, 7.2 mmol) in tetrahydrofuran (50 mL) was added lithiumtri-sec-butylborohydride (8.6 mL, 8.6 mmol, 1 M in tetrahydrofuran)dropwise. After 1.5 hours, the reaction mixture was warmed to roomtemperature, then cooled to 0° C., and 30% aqueous H₂O₂ was addeddropwise with caution until all gas evolution ceased. The mixture waswarmed to room temperature, poured into water, and extracted three timeswith ethyl acetate. The combined organics were washed with brine, driedover magnesium sulfate, filtered, and concentrated in vacuo to give thetitle compound (2.0 g, 100%), which was used without furtherpurification. MS(APCI+): m/z 280.2 (M+H)⁺, 236.1 (M-CO₂+H)⁺.

Step 4B: Preparation of 5-Fluoro-octahydro-cyclopenta[c]pyrrol-4-ol (B)

To a solution of5-Fluoro-4-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acidbenzyl ester (B) (0.38 g, 1.4 mmol) in tetrahydrofuran (10 mL) andmethanol (10 mL) in a Parr shaker was added 20% palladium hydroxide oncarbon (0.050 g), and hydrogen gas was introduced at 37 psi for 15hours. The reaction mixture was diluted with methanol, filtered throughdiatomaceous earth (Celite®), and concentrated in vacuo to afford thetitle compound (0.20 g, 100%) which was used without furtherpurification. MS)(APCI+): m/z 146.1 (M+H)⁺.

EXAMPLE 18 Preparation of 5-Fluoro-octahydro-cyclopenta[c]pyrrol-4-olStep 1: Preparation of 4-Benzoyloxy-5-fluoro-hexahydro-cyclopenta[c]pyrrole-2-carboxylic Acid Benzyl Ester

To a solution of triphenylphosphine (4.51 g, 17.2 mmol) intetrahydrofuran (20 mL) was added diisopropyl azodicarboxylate (3.4 mL,17 mmol). After 40 minutes, benzoic acid (2.10 g, 17.2 mmol) was added,followed by5-Fluoro-4-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acidbenzyl ester (A) (1.6 g, 5.7 mmol) in tetrahydrofuran (2 mL). Thetransfer was completed with 2×2 mL of tetrahydrofuran. The reactionmixture was heated at 70° C. for 48 hours, cooled to room temperature,and concentrated in vacuo. The resulting residue was purified on a 40LBiotage column using an ethyl acetate/hexanes gradient to afford thetitle compound (2.0 g, 91%). MS(APCI+): m/z 384.1 (M+H)⁺, 340.2(M−CO₂+H)⁺.

Step 2: Preparation of 5-Fluoro-4-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic Acid Benzyl Ester

To a cooled (0° C.) solution of4-benzoyloxy-5-fluoro-hexahydro-cyclopenta [c]pyrrole-2-carboxylic acidbenzyl ester (2.15 g, 5.61 mmol) in methanol (25 mL) was added sodiummethoxide (0.455 g, 8.42 mmol). After 2 hours, saturated aqueousammonium chloride was added, and the reaction mixture was warmed to roomtemperature and concentrated in vacuo. The residue was partitionedbetween water and dichloromethane. The aqueous phase was extracted twotimes with dichloromethane, and the combined organics were dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residue waspurified on a 40S Biotage column using an ethyl acetate/hexanes gradientto afford the title compound (0.33 g 21%). MS(APCI+): m/z 280.2 (M+H)⁺.

Step 3: Preparation of 5-Fluoro-octahydro-cyclopenta[c]pyrrol-4-ol

To a solution of5-fluoro-4-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acidbenzyl ester (0.33 g, 1.2 mmol) in ethanol (50 mL) in a Parr shaker wasadded 20% palladium on carbon (0.10 g), and hydrogen gas was introducedat 37 psi for 19 hours. The reaction mixture was diluted with methanol,filtered through diatomaceous earth (Celite®), and concentrated in vacuoto afford the title compound (0.17 g, 100%) which was used withoutfurther purification. MS: m/z 146.1 (M+H)⁺.

EXAMPLE 19 Preparation of 5-Fluoro-octahydro-cyclopenta[c]pyrrol-4-olStep 1: Preparation of 4-Benzoyloxy-5-fluoro-hexahydro-cyclopenta[c]pyrrole-2-carboxylic Acid Benzyl Ester

To a solution of triphenylphosphine (5.62 g, 21.4 mmol) intetrahydrofuran (20 mL) was added diisopropyl azodicarboxylate (4.2 mL,21 mmol). After 45 minutes, benzoic acid (2.62 g, 21.4 mmol) was added,followed by5-fluoro-4-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acidbenzyl ester (B) (2.0 g, 7.2 mmol) in tetrahydrofuran (2 mL). Thetransfer was completed with 2×2 mL of tetrahydrofuran. The reactionmixture was heated at 70° C. for 48 hours, and additionaltriphenylphosphine (2.81 g, 10.7 mmol), diisopropyl azodicarboxylate(2.1 mL, 11 mmol), and benzoic acid (1.31 g, 10.7 mmol) were added.Heating was continued for 24 hours, and the mixture was cooled to roomtemperature, and concentrated in vacuo. The residue was purified on a40L Biotage column using an ethyl acetate/hexanes gradient to afford thetitle compound (2.7 g, 100%). MS (APCI+): m/z 384.0 (M+H)⁺.

Step 2: Preparation of 5-Fluoro-4-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic Acid Benzyl Ester

To a cooled (0° C.) solution of4-benzoyloxy-5-fluoro-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acidbenzyl ester (2.7 g, 7.0 mmol) in methanol (40 mL) was added sodiummethoxide (0.59 g, 11 mmol). After 2 hours, glacial acetic acid (0.4 mL)was added, and the reaction mixture was warmed to room temperature andconcentrated in vacuo. The residue was partitioned between saturatedaqueous ammonium chloride and dichloromethane. The aqueous phase wasextracted two times with dichloromethane, and the combined organics weredried over magnesium sulfate, filtered, and concentrated in vacuo. Theresidue was purified on a 40S Biotage column using an ethylacetate/hexanes gradient to afford the title compound (0.37 g 19%).MS(APCI+): m/z 280.2 (M+H)⁺, 236.2 (M−CO₂+H).

Step 3: Preparation of 5-Fluoro-octahydro-cyclopenta[c]pyrrol-4-ol

To a solution of5-fluoro-4-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acidbenzyl ester (0.37 g, 1.3 mmol) in ethanol (20 mL) in a Parr shaker wasadded 5% palladium on carbon (0.50 g), and hydrogen gas was introducedat 37 psi for 16 hours. The reaction mixture was diluted with methanol,filtered through diatomaceous earth (Celite®), and concentrated in vacuoto afford the title compound (0.19 g, 100%) which was used withoutfurther purification. MS(APCI+): m/z 146.1 (M+H)⁺.

EXAMPLE 20 Preparation of5,5-Difluoro-octahydro-cyclopenta[c]pyrrol-4-ol Step 1: Preparation of5,5-Difluoro-4-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic AcidBenzyl Ester

To a cooled (−78° C.) solution of5-fluoro-4-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzylester (A) (5.38 g, 19.4 mmol) and zinc chloride (41 mL, 41 mmol, 1.0 Min diethyl ether) in tetrahydrofuran (100 mL) was added potassiumbiS(trimethylsilyl)amide (61 mL, 31 mmol, 0.5M in toluene), and thereaction mixture was stirred for 45 minutes. N-fluorobenzenesulfonimide(8.56 g, 27.1 mmol) in tetrahydrofuran (15 mL) was added, and thetransfer was completed with 2×2 mL of tetrahydrofuran. The reactionmixture was allowed to slowly warm to room temperature over 20 hours,and the mixture was diluted with saturated aqueous sodium bicarbonateand ethyl acetate. The aqueous phase was extracted two times with ethylacetate, and the combined organics were washed with brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residue wasabsorbed onto diatomaceous earth (Celite®) and purified on a 40L Biotagecolumn using an ethyl acetate/hexanes gradient to afford the titlecompound (3.2 g, 56%). MS(APCI+): m/z 296.1 (M+H)⁺.

Step 2: Preparation of 5,5-Difluoro-4-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic Acid Benzyl Ester

To a cooled (−78° C.) solution of5,5-difluoro-4-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acidbenzyl ester (2.6 g, 8.7 mmol) in tetrahydrofuran (30 mL) was addedlithium tri-sec-butylborohydride (10.5 mL, 10.5 mmol, 1 M intetrahydrofuran) dropwise, and the reaction mixture was slowly warmed toroom temperature over 20 hours. The mixture was cooled to 0° C., treatedwith 30% aqueous hydrogen peroxide dropwise with caution until all gasevolution ceased, warmed to room temperature and stirred for 30 minutes,and extracted three times with ethyl acetate. The combined organics werewashed with brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was purified on a 40S Biotage columnusing an ethyl acetate/hexanes gradient to afford the title compound(0.85 g, 33%). MS(APCI+): m/z 298.1 (M+H)⁺.

Step 3: Preparation of 5,5-Difluoro-octahydro-cyclopenta[c]pyrrol-4-ol

To a solution of5,5-difluoro-4-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acidbenzyl ester (0.71 g, 2.4 mmol) in ethanol (50 mL) in a Parr shaker wasadded 20% palladium on carbon (0.05 g), and hydrogen gas was introducedat 37 psi for 16 hours. The reaction mixture was diluted with methanol,filtered through diatomaceous earth (Celite®), and concentrated in vacuoto afford the title compound (0.39 g, 100%) which was used withoutfurther purification. MS(APCI+): m/z 164.1 (M+H)⁺.

EXAMPLE 21 Preparation of(7a-Hydroxymethyl-octahydro-isoindol-3a-yl)-methanol Step 1: Preparationof (2-Benzyl-7a-hydroxymethyl-octahydro-isoindol-3a-yl)-methanol

A solution of 4,5,6,7-Tetrahydro-isobenzofuran-1,3-dione (7.00 g, 46mmol) and benzyl-methoxymethyl-trimethylsilanylmethyl-amine (13.7 g,57.5 mmol) in dichloromethane (150 mL) was cooled to 0° C. and treatedwith catalytic trifluoroacetic acid (0.157 g, 1.38 mmol) and allowed tostir and slowly warm to ambient temperature. The mixture was stirredovernight then concentrated, diluted with ethylacetate, and the mixturewashed with aqueous saturated sodium bicarbonate solution. The organiclayer was then dried with sodium sulfate and filtered through a plug ofsilica with a 20/1 mixture of ethylacetate/triethylamine. The mixturewas then concentrated in vacuo. The resulting residue was then dissolvedin tetrahydrofuran (200 mL), under a nitrogen atomosphere (0° C.), andtreated with a diethylether solution of lithium aluminum hydride (150mL, 1.0 M) and allowed to slowly warm to ambient temperature and stirredovernight. The mixture was then treated with 5.6 mL of water and stirredfor 15 minutes. The mixture was then treated with 5.6 mL of 15% aqueoussodium hydroxide and stirred for 15 minutes before being treated with 17mL of water. The mixture was then stirred for 4 hr and filtered. Thefiltrate was then concentrated in vacuo to provide an oil (11.0 g).MS(APCI+): m/z 276 (M+H)⁺.

Step 2: Preparation of(7a-Hydroxymethyl-octahydro-isoindol-3a-yl)-methanol

To a solution of(2-benzyl-7a-hydroxymethyl-octahydro-isoindol-3a-yl)-methanol (11.0 g,39.9 mmol) in 100 mL of methanol in a Parr shaker was added 2.0 g of 20%palladium on carbon and hydrogen gas was introduced at 50 psi for 63hrs. The mixture was then diluted with additional methanol, filteredthrough diatomaceous earth (Celite (R)), and concentrated in vacuo toafford the title compound as an oil that was used without furtherpurification. MS(APCI+): m/z 186 (M+H)⁺

B. Coupling of Sidechain Precursors to Quinazolinedione Cores (cf.Scheme I)

EXAMPLE 22 General Procedure 1

A mixture of the pyrollidine (2 equiv), core (1 equiv) and1,1,3,3-tetramethylguanidine (3 equiv) in dimethylsulfoxide (0.5-1 mMol)is heated at 85-100° C. for 12-36 hours. The solution is poured intosaturated aqueous ammonium chloride and extracted with chloroform. Thecombined organic layers are dried with magnesium sulfate andconcentrated in vacuo. The product is purified on a silica gel columneluting with 0 to 10% methanol in dichloromethane to give the coupledproduct.Compounds Prepared According to This Procedure:

3-Amino-1-cyclopropyl-6-fluoro-7-[3-(hydroxy-oxazol-4-yl-methyl)-pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione;MS (APCI+): m/z 415.8 (M+H)⁺

3-Amino-1-cyclopropyl-7-[3-(2,2-difluoro-1-hydroxy-ethyl)-pyrrolidin-1-yl]-6-fluoro-5,8-dimethyl-1H-quinazoline-2,4-dione;MS (APCI+): m/z 384.1 (M+H)⁺

3-Amino-1-cyclopropyl-7-[3-(2,2-difluoro-1-hydroxy-ethyl)-pyrrolidin-1-yl]-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;MS (APCI+): m/z 399.1 (M+H)⁺

3-Amino-1-cyclopropyl-6-fluoro-7-[3-(2-hydroxy-1-hydroxymethyl-ethyl)-pyrrolidin-1-yl]-8-methyl-1H-quinazoline-2,4-dione;MS (APCI+): m/z 393 (M+H)⁺

3-Amino-1-cyclopropyl-7-[3-(1,2-dihydroxy-1-methyl-ethyl)-pyrrolidin-1-yl]-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;mp 136-138° C.

3-Amino-1-cyclopropyl-7-[3-(1,2-dihydroxy-1-methyl-ethyl)-pyrrolidin-1-yl]-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;MS (APCI+): m/z 393.1 (M+H)⁺

3-Amino-1-cyclopropyl-7-[3-(2,2-difluoro-1-hydroxy-propyl)-pyrrolidin-1-yl]-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;MS (APCI+): m/z 413.1 (M+H)⁺

3-Amino-1-cyclopropyl-6-fluoro-7-[3-(hydroxy-oxazol-2-yl-methyl)-pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione;MS (APCI+): m/z 431.0 (M+H)⁺

3-Amino-1-cyclopropyl-6-fluoro-7-[3-(hydroxy-oxazol-2-yl-methyl)-pyrrolidin-1-yl]-8-methyl-1H-quinazoline-2,4-dione;

3-Amino-1-cyclopropyl-6-fluoro-7-[3-(2-hydroxy-ethyl)-pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione;MS (APCI+): m/z 362.9 (M+H)⁺

3-Amino-1-cyclopropyl-6-fluoro-7-{3-[hydroxy-(1-hydroxymethyl-cyclopropyl)-methyl]-pyrrolidin-1-yl}-8-methoxy-1H-quinazoline-2,4-dione;MS (APCI+): m/z 419 (M+H)⁺

3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-[3-(2,2,2-trifluoro-1-hydroxy-ethyl)-pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;MS (APCI+): m/z 417 (M+H)⁺

3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methoxymethyl-pyrrolidin-1-yl)-1H-quinazoline-2,4-dione;MS (APCI+): m/z 363 (M+H)⁺

3-Amino-7-(3,4-mesobis-hydroxymethyl-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;MS (APCI+): m/z 379 (M+H)⁺

3-Amino-7-(3,4-mesobis-hydroxymethyl-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;MS (APCI+): m/z 379 (M+H)⁺

3-Amino-7-(3,4-bis-hydroxymethyl-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;MS (APCI+): m/z 379 (M+H)⁺

3-Amino-1-cyclopropyl-6-fluoro-7-(3-hydroxymethyl-4-methoxymethyl-pyrrolidin-1-yl)-8-methyl-1H-quinazoline-2,4-dione;

3-Amino-7-[3,4-bis-(2-hydroxy-ethyl)-pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;MS (APCI+): m/z 407 (M+H)⁺

3-Amino-1-cyclopropyl-7-(3,4-mesodihydroxy-pyrrolidin-1-yl)-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;MS (APCI+): m/z 351 (M+H)

3-Amino-1-cyclopropyl-6-fluoro-7-(3-hydroxymethyl-4-trifluoromethyl-pyrrolidin-1-yl)-8-methyl-1H-quinazoline-2,4-dione;MS (APCI+): m/z 417 (M+H)⁺

3-Amino-1-cyclopropyl-6-fluoro-7-(3-fluoro-4-hydroxymethyl-pyrrolidin-1-yl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione;MS (APCI+): m/z 367 (M+H)⁺

3-Amino-1-cyclopropyl-6-fluoro-7-(4-hydroxymethyl-3,3-dimethyl-pyrrolidin-1-yl)-8-methyl-1H-quinazoline-2,4-dione;MS (APCI+): m/z 377 (M+H)⁺

3-Amino-7-(3,4-bis-hydroxymethyl-3,4-dimethyl-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;MS (APCI+): m/z 407.2 (M+H)⁺

3-Amino-1-cyclopropyl-6-fluoro-7-(4-hydroxy-4-hydroxymethyl-hexahydro-cyclopenta[c]pyrrol-2-yl)-8-methyl-1H-quinazoline-2,4-dione;mp 172-174° C.

D. Pharmaceutical Formulations

EXAMPLE 23

The following illustrates representative pharmaceutical dosage forms,containing a compound of Formula I (“Invention Compound”), fortherapeutic or prophylactic use in humans. (i) Tablet mg/tablet‘Invention Compound’ 25.0 Lactose 50.0 Corn Starch (for mix) 10.0 CornStarch (paste) 10.0 Magnesium Stearate (1%) 3.0 300.0

The invention compound, lactose, and corn starch (for mix) are blendedto uniformity. The corn starch (for paste) is suspended in 200 mL ofwater and heated with stirring to form a paste. The paste is used togranulate the mixed powders. The wet granules are passed through a No. 8hand screen and dried at 80° C. The dry granules are lubricated with the1% magnesium stearate and pressed into a tablet. Such tablets can beadministered to a human from one to four times a day for treatment ofpathogenic bacterial infections. (ii) Tablet mg/capsule ‘InventionCompound 10.0 Colloidal Silicon Dioxide 1.5 Lactose 465.5 PregelatinizedStarch 120.0 Magnesium Stearate (1%) 3.0 600.0

(iii) Preparation for Oral Solution Amount ‘Invention Compound’ 400 mgSorbitol Solution (70% N.F.) 40 mL Sodium Benzoate 20 mg Saccharin 5 mgCherry Flavor 20 mg Distilled Water q.s. 100 mL

The sorbitol solution is added to 40 mL of distilled water, and theinvention compound is dissolved therein. The saccharin, sodium benzoate,flavor, and dye are added and dissolved. The volume is adjusted to 100mL with distilled water. Each milliliter of syrup contains 4 mg ofinvention compound.

(iv) Parenteral Solution

In a solution of 700 mL of propylene glycol and 200 mL of water forinjection is suspended 20 g of an invention compound. After suspensionis complete, the pH is adjusted to 6.5 with 1 N hydrochloric acid, andthe volume is made up to 1000 mL with water for injection. TheFormulation is sterilized, filled into 5.0 mL ampoules each containing2.0 mL, and sealed under nitrogen. (v) Injection 1 (1 mg/mL) Amount‘Invention Compound’ 1.0 Dibasic Sodium Phosphate 12.0  Monobasic SodiumPhosphate 0.7 Sodium Chloride 4.5 N Sodium hydroxide solution q.s. (pHadjustment to 7.0-7.5) Water for injection q.s. ad 1 mL

(vi) Injection 2 (10 mg/mL) Amount ‘Invention Compound’ 10.0 DibasicSodium Phosphate 1.1 Monobasic Sodium Phosphate 0.3 Polyethylene glyco400 200.0 N hydrochloric acid solution q.s. (pH adjustment to 7.0-7.5)Water for injection q.s. ad 1 mL

(vii) Injection 2 (10 mg/mL) Amount ‘Invention Compound’ 20.0 Oleic Acid10.0 Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0Dichlorotetrafluoroethane 5,000.0.

All patents, and patent documents are incorporated by reference herein,as though individually incorporated by reference. The invention and themanner and process of making and using it, are now described in suchfull, clear, concise and exact terms as to enable any person skilled inthe art to which it pertains, to make and use the same. It is to beunderstood that the foregoing describes preferred embodiments of thepresent invention and that modifications may be made therein withoutdeparting from the spirit or scope of the present invention as set forthin the claims. To particularly point out and distinctly claim thesubject matter regarded as invention, the following claims conclude thisspecification.

1. A compound of formula I

or a pharmaceutically acceptable salt thereof, wherein: X is N or C,provided that when X is N, R₅ is absent; R₁ is (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, halo(C₃-C₆)cycloalkyl aryl, andheteroaryl; R₂ is H,

NH(C₁-C₆)alkyl, NH(C₃-C₆)cycloalkyl, NH-heteroaryl, NHSO₂—(C₁-C₆)alkyl,NHSO₂-aryl, NHSO₂-heteroaryl,

 wherein, Q is O or is absent, and R_(2a) and R_(2a′) are eachindependently H or (C₁-C₆)alkyl, or taken together with the carbons towhich they are attached form a 3, 4, 5, or 6-membered substituted orunsubstituted ring, and R_(2b) is (C₁-C₆)alkyl, aryl, or heteroaryl,

 wherein R_(2a) and R_(2a′) are as defined above,

 wherein

 indicates the point of attachment, p is 0 or 1, and R₂ c is H,(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, aryl, heterocyclo, heteroaryl, or

 wherein R_(2a), R_(2b), and Q are as defined above, n is an integerfrom 0 to 10, and Y is OH, OPO(OH)₂, OPO(O(C₁-C₆)alkyl)₂, orNR_(2d)R_(2e), wherein R_(2d) and R_(2e) are each independently H,(C₁-C₆)alkyl, or (C₃-C₇)cycloalkyl,

 wherein Q is O or 1, R_(2f) and R_(2f) are each independently H,(C₁-C₆)alkyl, aryl, or heteroaryl, or taken together with the carbon towhich they are attached form a 3, 4, 5, or 6 membered ring, and R_(2g)is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, aryl, or heterocyclo, or heteroaryl;R₃, R₄, and R₅ are each independently H, halo, NH₂, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, or halo(C₁-C₆)alkoxy; R_(c), R_(d),R_(e), R_(f), and R_(g) are each independently H, halo, (C₁-C₆)alkyl,OH, OPO(OH)₂, OPO(O(C₁-C₆)alkyl)₂, (C₁-C₆)alkyl-O °,

 wherein

 indicates the point of attachment and Q is O or is absent,R_(ii)O(C₁-C₆)alkyl, R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group that does not contain an NH, and x is aninteger of from 0 to 10;

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10, wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂, or(C₁-C₆)alkyl

 as defined above; provided that 3 or fewer of R_(c), R_(d), R_(e), andR_(f) are H; or R_(c) and R_(e), together with the carbons to which theyare attached, form a substituted or unsubstituted 4, 5, or 6-memberedring containing 0, 1, 2, or 3 heteroatoms selected from NHN(C₁-C₆)alkyl, S, or O; or R_(c) and R_(d), or R_(e) and R_(f),independently, together with the carbon to which they are attached, forma substituted or unsubstituted 3, 4, 5, or 6-membered ring containing 0,1, 2, or 3 heteroatoms selected from NH, N(C₁-C₆)alkyl, S, or O.
 2. Thecompound of claim 1, wherein R₁ is (C₁-C₆)cycloalkyl andhalo(C₁-C₆)cycloalkyl, aryl, or heteroaryl; R₂ is NH₂; R₃ is H or NH₂;R₄ is H or halo; and R₅ is halo, methyl, trifluoromethyl, methoxy,fluoromethoxy, difluoromethoxy, or trifluoromethoxy.
 3. The compound ofclaim 1, wherein R₁ is cyclopropyl, fluorocyclopropyl,

R₂ is NH₂; R₃ is H or NH₂; R₄ is H or F; and R₅ is halo, methyl,trifluoromethyl, or methoxy.
 4. The compound of claim 1, wherein R₁, R₃,and R₅ are as provided in the following structures, wherein R₂ is H orNH₂, R₄ is H or F and A is


5. The compound in claim 4 wherein R_(c), R_(d), R_(f), and R_(g) are Hin A, and R_(c) is OPO(OH)₂, OPO(O(C₁-C₆)alkyl)₂,

 wherein

 indicates the point of attachment and Q is O or is absent,

 wherein

 indicates the point of attachment, R_(i) is H or (C₁-C₆)alkyl, and c isan integer having a value of from 1 to 10, R_(ii)O(C₁-C₆)alkyl,R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group, that does not contain an NH, and x isan integer of from 0 to 10;

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10; wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂,

 as defined above, or

 as defined above.
 6. The compound of claim 4 wherein A is

and includes the following structures, wherein

indicates the point of attachment.


7. The compound of claim 4, wherein R_(e), R_(f), and R_(g) are H, andR_(c) is OH, OPO(OH)₂, OPO(O(C₁-C₆)alkyl)₂,

 wherein

 indicates the point of attachment and Q is O or is absent,

 wherein

 indicates the point of attachment, R_(i) is H or (C₁-C₆)alkyl, and c isan integer having a value of from 1 to 10, R_(ii)O(C₁-C₆)alkyl,R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group, and x is an integer of from 0 to 10;

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10; wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂,

 as defined above; and R_(d) is halo, (C₁-C₆)alkyl, R_(ii)O(C₁-C₆)alkyl,R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment and Q is or is absent.
 8. Thecompound of claim 4, wherein A is

wherein

indicates the point of attachment, and includes


9. The compound of claim 4 wherein R_(d), R_(f), and R_(g) are H, in A,and R_(c) is OH, OPO(OH)₂, OPO(O(C₁-C₆)alkyl)₂,

 wherein

 indicates the point of attachment and Q is O or is absent,R_(ii)O(C₁-C₆)alkyl, R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group that does not contain an NH, and x is aninteger of from 0 to 10;

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10; wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂,

 as defined above; and R_(e) is halo

wherein

 indicates the point of attachment and Q is O or is absent,R_(ii)O(C₁-C₆)alkyl, R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group that does not contain an NH, and x is aninteger of from 0 to 10;

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10; wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂, or

 as defined above.
 10. The compound of claim 4, wherein A is

wherein

indicates the point of attachment, and includes


11. The compound of claim 4, wherein R_(d), and R_(g) are H and R_(c) isOPO(OH)₂, OPO(O(C₁-C₆)alkyl)₂,

 wherein

 indicates the point of attachment and Q is O or is absent,R_(ii)O(C₁-C₆)alkyl, R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group that does not contain an NH, and x is aninteger of from 0 to 10;

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10, wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂,

 as defined above; and R_(c) and R_(f) are each independently(C₁-C₆)alkyl or together with the carbon to which they are attached,form a substituted or unsubstituted 3, 4, 5, or 6-membered ringcontaining 0, 1, 2, or 3 heteroatoms selected from NH, N(C₁-C₆)alkyl, S,or O.
 12. The compound of claim 4, wherein A is

wherein

indicates the point of attachment, and includes


13. The compound of claim 4 wherein R_(c) and R_(e) are eachindependently H, OH, OPO(OH)₂, OPO(O(C₁-C₆)alkyl)₂,

 wherein

 indicates the point of attachment and Q is O or is absent,R_(ii)O(C₁-C₆)alkyl, R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group that does not contain an NH, and x is aninteger of from 0 to 10;

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10, wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂,

 as defined above; and R_(d) and R_(f) are each independently(C₁-C₆)alkyl, or taken together with the carbons to which they areattached form a substituted or unsubstituted 4, 5, or 6 membered ring,optionally containing one heteroatom selected from NH, N(C₁-C₆)alkyl, S,or O.
 14. The compound of claim 13, wherein


15. The compound of claim 4, wherein R_(d) and R_(f) are eachindependently H, halo (C₁-C₆)alkyl, OH, OPO(OH)₂, OPO(O(C₁-C₆)alkyl)₂,

 wherein

 indicates the point of attachment and Q is O or is absent,

 wherein

 indicates the point of attachment, R_(i) is H or (C₁-C₆)alkyl, and c isan integer having a value of from 1 to 10, R_(ii)O(C₁-C₆)alkyl,R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10; wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂,

 as defined above; R_(c) and R_(e), together with the carbons to whichthey are attached, form a substituted or unsubstituted 4, 5, or6-membered ring containing 0, 1, 2, or 3 heteroatoms selected from NH,N(C₁-C₆)alkyl), NH, N(C₁-C₆)alkyl, S, or O.
 16. The compound of claim15, wherein A is

wherein

indicates the point of attachment, and includes


17. A compound of claim 1 having formula II, formula III, formula IV,formula V, formula VI or formula VII as follows: formula II

or a pharmaceutically acceptable salt thereof, wherein X is N or C,provided that when X is N, R₅ is absent; R₁ is (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, halo(C₃-C₆)cycloalkyl aryl, andheteroaryl; R₂ is H, NH₂,

NH(C₁-C₆)alkyl, NH(C₃-C₆)cycloalkyl, NH-heteroaryl, NHSO₂—(C₁-C₆)alkyl,NHSO₂-aryl, NHSO₂-heteroaryl,

 wherein, Q is O or is absent, and R_(2a) and R_(2a′) are eachindependently H or (C₁-C₆)alkyl, or taken together with the carbons towhich they are attached form a 3, 4, 5, or 6-membered substituted orunsubstituted ring, and R_(2b) is (C₁-C₆)alkyl, aryl, or heteroaryl,

 wherein R_(2a) and R_(2a′) are as defined above,

 wherein

 indicates the point of attachment, p is 0 or 1, and R₂ c is H,(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, aryl, heterocyclo, heteroaryl, or

 wherein R_(2a), R_(2b), and Q are as defined above, n is an integerfrom 0 to 10, and Y is OH, OP(O)(OH)₂, OPO(O(C₁-C₆)alkyl)₂, orNR_(2d)R_(2e), wherein R_(2d) and R_(2e) are each independently H,(C₁-C₆)alkyl, or (C₃-C₇)cycloalkyl,

 wherein q is 0 or 1, R_(2f) and R_(2f′) are each independently H,(C₁-C₆)alkyl, aryl, or heteroaryl, or taken together with the carbon towhich they are attached form a 3, 4, 5, or 6 membered ring, and R_(2g)is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, aryl, or heterocyclo, or heteroaryl;R₃, R₄, and R₅ are each independently H, halo, NH₂, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, or halo(C₁-C₆)alkoxy; and R_(c) isOPO(OH)₂, OPO(O(C₁-C₆)alkyl)₂,

 wherein

 indicates the point of attachment and Q is O or is absent,R_(ii)O(C₂-C₆)alkyl, R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group that does not contain an NH, and x is aninteger of from 0 to 10;

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10, wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂, or

 as defined above; or a compound of formula III

or a pharmaceutically acceptable salt thereof, wherein X is N or C,provided that when X is N, R₅ is absent; R₁ is (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, halo(C₃-C₆)cycloalky aryl, andheteroaryl R₂ is H, NH₂,

NH(C₁-C₆)alkyl, NH(C₃-C₆)cycloalkyl, NH-heteroaryl, NHSO₂-(C₁-C₆)alkyl,NHSO₂-aryl, NHSO₂-heteroaryl,

 wherein, Q is O or is absent, and R_(2a) and R_(2a′) are eachindependently H or (C₁-C₆)alkyl, or taken together with the carbons towhich they are attached form a 3, 4, 5, or 6-membered substituted orunsubstituted ring, and R_(2b) is (C₁-C₆)alkyl, aryl, or heteroaryl,

 wherein R_(2a) and R_(2a′) are as defined above,

 , wherein

 indicates the point of attachment, p is 0 or 1, and R_(c) is H,(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, heterocyclo, heteroaryl, or

 wherein R_(2a), R_(2b), and Q are as defined above, n is an integerfrom 0 to 10, and Y is OH, OPO(O(C₁-C₆)alkyl)₂, OPO(OH)₂, orNR_(2d)R_(2e), wherein R_(2d) and R_(2e) are each independently H,(C₁-C₆)alkyl, or (C₃-C₇)cycloalkyl,

 wherein q is 0 or 1, R_(2f) and R_(2f′) are each independently H,(C₁-C₆)alkyl, aryl, or heteroaryl, or taken together with the carbon towhich they are attached form a 3, 4, 5, or 6 membered ring, and R_(2g)is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, aryl, or heterocyclo, or heteroaryl;R₃, R₄, and R₅ are each independently H, halo, NH₂, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, or halo(C₁-C₆)alkoxy; and R_(c) is OH,OPO(OH)₂, OPO(O(C₁-C₆)alkyl)₂,

 wherein

 indicates the point of attachment and Q is O or is absent,R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycoalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group that does not contain an NH, and x is aninteger of from 0 to 10,

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10, wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂, or

 as defined above; and R_(d) is halo, (C₁-C₆)alkyl, R_(ii)O(C₁-C₆)alkyl,R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—, or

 wherein

 indicates the point of attachment and Q is O or is absent; or acompound of formula IV

or a pharmaceutically acceptable salt thereof, wherein X is N or C,provided that when X is N, R₅ is absent, R₁ is (C₁-C₆ alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)cycloalkyl halo(C₃-C₆)cycloalkyl aryl, andheteroaryl; R₂ is H, NH₂,

NH(C₁-C₆)alkyl, NH(C₃-C₆)cycloalkyl, NH-heteroaryl, NHSO₂-(C₁-C₆)alkyl,NHSO₂-aryl, NHSO₂-heteroaryl,

 wherein, Q is O or is absent, and R_(2a) and R_(2a′) are eachindependently H or (C₁-C₆)alkyl, or taken together with the carbons towhich they are attached form a 3, 4, 5, or 6-membered substituted orunsubstituted ring, and R_(2b) is (C₁-C₆)alkyl, aryl, or heteroaryl,

 wherein R_(2a) and R_(2a′) are as defined above,

 wherein

 indicates the point of attachment, p is 0 or 1, and R_(2c) is H,(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, aryl, heterocyclo, heteroaryl, or

 wherein R_(2a), R_(2b), and Q are as defined above, n is an integerfrom 0 to 10, and Y is OH, OP(O)(O(C₁-C₆)alkyl)₂, OP(O)(OH)₂, orNR_(2d)R_(2e), wherein R_(2d) and R_(2e) are each independently H,(C₁-C₆)alkyl, or (C₃-C₇)cycloalkyl,

 wherein q is 0 or 1, R_(2f) and R_(2f′) are each independently H,(C₁-C₆)alkyl, aryl, or heteroaryl, or taken together with the carbon towhich they are attached form a 3, 4, 5, or 6 membered ring, and R_(2a)is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, aryl, or heterocyclo, or heteroaryl;R₃, R₄, and R₅ are each independently H, halo, NH₂, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, or halo(C₁-C₆)alkoxy; and R_(c) is OH,OPO(OH)₂, OPO(O(C₁-C₆)alkyl)₂,

 wherein

 indicates the point of attachment and Q is O or is absent,R_(ii)O(C₁-C₆)alkyl. R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₁-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group) that does not contain an NH, and x isan integer of from 0 to 10;

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10; wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂,

 as defined above; and R_(e) is halo

wherein

 indicates the point of attachment and Q is O or is absent,R_(ii)(C₁-C₆)alkyl, R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₁-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group that does not contain an NH, and x is aninteger of from 0 to 10;

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10: wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂, or

 as defined above; or a compound of formula V

or a pharmaceutically acceptable salt thereof, wherein X is N or C,provided that when X is N, R₅ is absent; R₁ is (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₃-C₆)Cycloalkyl, halo(C₃-C₆)cycloalkyl aryl, andheteroaryl; R₂ is H, NH₂,

NH(C₁-C₆)alkyl, NH(C₃-C₆)cycloalkyl, NH-heteroaryl, NHSO₂—(C₁-C₆)alkyl,NHSO₂-aryl, NHSO₂-heteroaryl,

 wherein, Q is O or is absent, and R_(2a) and R_(2a′) are eachindependently H or (C₁-C₆)alkyl, or taken together with the carbons towhich they are attached form a 3, 4, 5, or 6-membered substituted orunsubstituted ring, and R_(2b) C₁-C₆)alkyl, aryl, or heteroaryl,

 wherein R_(2a) and R_(2a′) at are as defined above,

 wherein

 indicates the point of attachment, p is 0 or 1, and R_(2c) is H,(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, heterocyclo, heteroaryl, or

 wherein R_(2a), R_(2b), and Q are as defined above, n is an integerfrom 0 to 10, and Y is OH, OP(O)(O(C₁-C₆)alkyl)₂, OP(O)(OH)₂, orNR_(2d)R_(2e), wherein R_(2d) and R_(2e) are each independently H,(C₁-C₆)alkyl, or (C₃-C₇)cycloalkyl,

 wherein q is 0 or 1, R_(2f) and R_(2f′) are each independently H,(C₁-C₆)alkyl, aryl, or heteroaryl, or taken together with the carbon towhich they are attached form a 3, 4, 5, or 6 membered ring, and R_(2g)is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, aryl, or heterocyclo, or heteroaryl;R₃, R₄, and R₅ are each independently H, halo, NH₂, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, or halo(C₁-C₆)alkoxy; and R_(c) is OH,OPO(OH)₂, OPO(O(C₁-C₆)alkyl)₂,

 wherein

 indicates the point of attachment and Q is O or is absent,R_(ii)O(C₁-C₆)alkyl, R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₁-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group that does not contain an NH, and x is aninteger of from 0 to 10,

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10, wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl,

 as defined above; and R_(e) and R_(f) are each independently halo,

wherein

 indicates the point of attachment and Q is O or is absent,R_(ii)O(C₁-C₆)alkyl, R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)haloalkyl-O—, R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group that does not contain an NH, and x is aninteger of from 0 to 10;

 wherein

 indicates the point of attachment, het is as defined above, and v is aninteger of from 1 to 10; wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂, or

 as defined above, or R_(e) and R_(f) taken together with the carbons towhich the are attached form an optionally substituted 3, 4, 5, 6membered ring; or a compound of formula VI

or a pharmaceutically acceptable salt thereof, wherein X is N or C,provided that when X is N, R₅ is absent; R₁ is (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)cycloalkyl, halo(C₃-C₆)cycloalkyl aryl, andheteroaryl; R₂ is H, NH₂,

NH(C₁-C₆)alkyl, NH(C₁-C₆)cycloalkyl, NH-heteroaryl, NHSO₂—(C₁-C₆)alkyl,NHSO₂-aryl, NHSO₂-heteroaryl,

 wherein, Q is O or is absent, and R_(2a) and R_(2a′) are eachindependently H or (C₁-C₆)alkyl, or taken together with the carbons towhich they are attached form a 3, 4, 5, or 6-membered substituted orunsubstituted ring, and R_(2b) is C₁-C₆)alkyl, aryl, or heteroaryl,

 wherein R_(2a) and R_(2a′) are as defined above,

 wherein

 indicates the point of attachment, p is 0 or 1, and R₂ is H(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, aryl, heterocyclo, heteroaryl, or

 wherein R_(2a), R_(2b), and Q are as defined above, n is an integerfrom 0 to 10, and Y is OH, OP(O)(O(C₁-C₆)alkyl)₂, OP(O)(OH)₂, orNR_(2d)R_(2e), wherein R_(2d) and R_(2e) are each independently H,(C₁-C₆)alkyl, or (C₃-C₇)cycloalkyl,

 wherein q is 0 or 1, R_(2f) and R_(2f′) are each independently H,(C₁-C₆)alkyl, aryl, or heteroaryl, or taken together with the carbon towhich they are attached form a 3, 4, 5, or 6 membered ring, and R_(2g)is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, aryl, or heterocyclo, or heteroaryl;R₃, R₄, and R₅ are each independently H, halo, NH₂, halo(C₁-C₆ alkyl,(C₁-C₆)alkoxy, or halo(C₁-C₆)alkoxy; and R_(c) is OH, OPO(OH)₂,OPO(O(C₁-C₆)alkyl)₂,

 wherein

 indicates the point of attachment and Q is O or is absent,R_(ii)O(C₁-C₆)alkyl, R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₁-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group that does not contain an NH, and x is aninteger of from 0 to 10;

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10, wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂,

 as defined above; and R_(e) is halo

wherein

 indicates the point of attachment and Q is O or is absent,R_(ii)O(C₁-C₆)alkyl, R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₁-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alky-O—, R_(ii)O(C₁-C₆)cycloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group that does not contain an NH, and x is aninteger of from 0 to 10,

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10; wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂, or

 as defined above; and R_(d) and R_(f) are each independently(C₁-C₆)alkyl, or a compound of formula VII

or a pharmaceutically acceptable salt thereof, wherein X is N or C,provided that when X is N, R₅ is absent; Z is absent or is a substitutedor unsubstituted carbon linker 1, 2 0r 3 atoms in length; R₁ is(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl. halo(C₃-C₆)cycloalkylaryl, and heteroaryl; (C₁-C₆)alkyl R₃, R₄, and R₅ are each independentlyH, halo, NH₂, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy; orhalo(C₁-C₆)alkoxy; and R_(c) and R_(f) are each independently H or(C₁-C₆)alkyl; R_(h), R_(i) and R_(j) are each independently H, OH,OPO(OH)₂, OPO(O(C₁-C₆)alkyl)₂,

 wherein

 indicates the point of attachment and Q is O or is absent,R_(ii)O(C₁-C₆)alkyl, R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group that does not contain an NH, and x is aninteger of from 0 to 10;

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10; wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂,

 as defined above; and R_(i) is H or (C₁-C₆)alkyl.
 18. The compound ofclaim 17, wherein: R₁ is (C₁-C₆)cycloalkyl and halo(C₁-C₆)cycloalkyl,aryl, or heteroaryl; R₂ is NH₂; R₃ is H or NH₂; R₄ is H or halo; and R₅is halo, methyl, trifluoromethyl, methoxy, fluoromethoxy,difluoromethoxy, or trifluoromethoxy.
 19. The compound of claim 18,wherein

is

wherein

indicates the point of attachment.
 20. The compound of claim 18, whereinR_(c) in

is OH, OPO(OH)₂, OPO(O(C₁-C₆)alkyl)₂,

 wherein

 indicates the point of attachment and Q is O or is absent,

 wherein

 indicates the point of attachment, R_(i) is H or (C₁-C₆)alkyl, and c isan integer having a value of from 1 to 10, R_(ii)C₁-C₆)alkyl,R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group, and x is an integer of from 0 to 10;

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10; wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂,

 as defined above; in

R_(d) is H; and R_(c) is OH, OPO(OH)₂, OPO(O(C₁-C₆)alkyl)₂,

 wherein

 indicates the point of attachment and Q is O or is absent,R_(ii)O(C₁-C₆)alkyl, R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₄-C₆)cycloalkyl.R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₁-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group that does not contain an NH, and x is aninteger of from 0 to 10;

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10; wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂,

 as defined above; or in

R_(c) is OPO(OH)₂, OPO(O(C₁-C₆)alkyl)₂,

 wherein

 indicates the point of attachment and Q is O or is absent,R_(ii)O(C₁-C₆)alkyl, R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group that does not contain an NH, and x is aninteger of from 0 to 10;

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10, wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂,

 as defined above; and R_(e) is (C₁-C₆)alkyl or together with the carbonto which it is attached, form a substituted or unsubstituted 3, 4, 5, or6-membered ring containing 0, 1, 2, or 3 heteroatoms selected from NH,N(C₁-C₆)alkyl, S, or O, or in

R_(c) and Re are each independently H, OH, OPO(OH)₂,OPO(O(C₁-C₆)alkyl)₂,

 wherein

 indicates the point of attachment and Q is O or is absent,R_(ii)O(C₁-C₆)alkyl, R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group that does not contain an NH, and x is aninteger of from 0 to 10;

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10, wherein R_(ii) is H  (C₁-C₆)alkyl,  PO(OH)₂, PO(O(C₁-C₆)alkyl)₂,

 as defined above; and R_(f) is each independently (C₁-C₆)alkyl, ortaken together with the carbon to which it is attached forms asubstituted or unsubstituted 4, 5, or 6 membered ring, optionallycontaining one heteroatom selected from NH, N(C₁-C₆)alkyl, S, or O; orin

R_(d) and R_(f) are each independently H, halo (C₁-C₆)alkyl, OH,OPO(OH)₂, OPO(O(C₁-C₆)alkyl)₂,

 wherein

 indicates the point of attachment and Q is O or is absent,

 wherein

 indicates the point of attachment, R_(i) is H or (C₁-C₆)alkyl, and c isan integer having a value of from 1 to 10, R_(ii)O(C₁-C₆)alkyl,R_(ii)O(C₁-C₆)haloalkyl. R_(ii)O(C₁-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10; wherein R_(ii) is H, (C₁-C₆)alkyl, PO(OH)₂,PO(O(C₁-C₆)alkyl)₂,

 as defined above; R_(c) and R_(e), together with the carbons to whichthey are attached, form a substituted or unsubstituted 4, 5, or6-membered ring containing 0, 1, 2, or 3 heteroatoms selected from NH,N(C₁-C₆)alkyl), NH, N(C₁-C₆)alkyl, S, or O.
 21. A compound of claim 1which is3-Amino-1-cyclopropyl-6-fluoro-7-(3-hydroxymethyl-pyrrolidin-1-yl)-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-7-[3-(hydroxy-oxazol-4-yl-methyl)-pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-7-[3-(2,2-difluoro-1-hydroxy-ethyl)-pyrrolidin-1-yl]-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-7-[3-(furan-2-yl-hydroxy-methyl)-pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-7-[3-(1,2-dihydroxy-1-methyl-ethyl)-pyrrolidin-1-yl]-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-7-[3-(hydroxy-oxazol-2-yl-methyl)-pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-7-[3-(hydroxy-oxazol-2-yl-methyl)-pyrrolidin-1-yl]-8-methyl-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-7-[3-(2,2-difluoro-1-hydroxy-propyl)-pyrrolidin-1-yl]-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-7-[3-(2-hydroxy-ethyl)-pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-7-{3-[hydroxy-(1-hydroxymethyl-cyclopropyl)-methyl]-pyrrolidin-1-yl}-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-7-[3-(1,2-dihydroxy-ethyl)-pyrrolidin-1-yl]-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-[3-(2,2,2-trifluoro-1-hydroxy-ethyl)-pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methoxymethyl-pyrrolidin-1-yl)-1H-quinazoline-2,4-dione;

3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-[3-methyl-3-(3,3,3-trifluoro-1-hydroxy-propyl)-pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;

3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-[3-methyl-3-(3,3,3-trifluoro-1-hydroxy-propyl)-pyrrolidin-1-yl]-1H-quinazoline-2,4-dione,

3-Amino-1-cyclopropyl-6-fluoro-7-[3-methyl-3-(3,3,3-trifluoro-1-hydroxy-propyl)-pyrrolidin-1-yl]-1H-pyrido[2,3-d]pyrimidine-2,4-dione;

3-Amino-7-(3,3-bis-hydroxymethyl-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;

3-Amino-7-(3,3-bis-hydroxymethyl-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;

3-Amino-7-(3,3-bis-hydroxymethyl-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;

3-Amino-7-(3,4-mesobis-hydroxymethyl-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;

3-Amino-1-cyclopropyl-6-fluoro-7-(7-hydroxymethyl-5-aza-spiro[2,4]hept-5-yl)-8-methoxy-1H-quinazoline-2,4-dione:

3-Amino-1-cyclopropyl-6-fluoro-7-(7-hydroxymethyl-5-aza-spiro[2,4]hept-5-yl)-8-methyl-1H-quinazoline-2,4-dione;

3-Amino-1-cyclopropyl-6-fluoro-7-(7-hydroxymethyl-5-aza-spiro[2,4]hept-5-yl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione;

3-Amino-1-cyclopropyl-7-[7-(1,2-dihydroxy-ethyl)-5-aza-spiro[2.4]hept-5-yl]-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;

3-Amino-1-cyclopropyl-7-[7-(1,2-dihydroxy-ethyl)-5-aza-spiro[2.4]hept-5-yl]-6-fluoro-8-methyl-1H-quinazoline-2,4-dione,

3-Amino-1-cyclopropyl-7-[7-(1,2-dihydroxy-ethyl)-5-aza-spiro[2,4]hept-5-yl]-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;

3-Amino-1-cyclopropyl-6-fluoro-7-(4-hydroxymethyl-3,3-dimethyl-pyrrolidin-1-yl)-8-methoxy-1H-quinazoline-2,4-dione;

3-Amino-1-cyclopropyl-6-fluoro-7-(4-hydroxymethyl-3,3-dimethyl-pyrrolidin-1-yl)-8-methyl-1H-quinazoline-2,4-dione,

3-Amino-1-cyclopropyl-6-fluoro-7-(4-hydroxymethyl-3,3-dimethyl-pyrrolidin-1-yl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione;

3-Amino-7-(3,4-transbis-hydroxymethyl-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;

3-Amino-1-cyclopropyl-7-(3,4-mesodihydroxy-pyrrolidin-1-yl)-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;

3-Amino-7-[3,4-bis-meso(2-hydroxy-ethyl)-pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;

3-Amino-1-cyclopropyl-6-fluoro-7-(3-fluoro-4-hydroxymethyl-pyrrolidin-1-yl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione;

3-Amino-7-(3,4-bis-hydroxymethyl-3,4-dimethyl-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;

3-Amino-7-(3,4-bis-hydroxymethyl-3,4-dimethyl-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;

3-Amino-1-cyclopropyl)-6-fluoro-7-(4-hydroxy-4-hydroxymethyl-hexahydro-cyclopenta[c]pyrrol-2-yl)-8-methyl-1H-quinazoline-2,4-dione;or

3-Amino-1-cyclopropyl-6-fluoro-7-(4-hydroxy-4-hydroxymethyl-hexahydro-cyclopenta[c]pyrrol-2-yl)-8-methoxy-1H-quinazoline-2,4-dione.22. (canceled)
 23. The compound of claim 17, wherein: R₁ is cyclopropyl,fluorocyclopropyl,

R₂ is NH₂; R₃ is H or NH₂; R₄ is H or F; and R₅ is halo, methyl,trifluoromethyl, or methoxy.
 24. (canceled)
 25. (canceled) 26.(canceled)
 27. (canceled)
 28. The compound of claim 17, wherein: R₁, R₃,and R₅ are as provided in the following structures, wherein R₂ is H orNH₂, R₄ is H or F and A is


29. (canceled)
 30. (canceled)
 31. (canceled)
 32. (canceled) 33.(canceled)
 34. (canceled)
 35. (canceled)
 36. (canceled)
 37. (canceled)38. (canceled)
 39. (canceled)
 40. (canceled)
 41. (canceled) 42.(canceled)
 43. The compound of claim 17, wherein when the compound isformula VII R₁ is (C₁-C₆)cycloalkyl, halo(C₁-C₆)cycloalkyl, aryl, orheteroaryl; R₂ is H or NH₂; R₃ is H or NH₂; R₄ is H or halo; and R₅ ishalo, methyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,or trifluoromethoxy.
 44. The compound of claim 43, wherein R₁ iscyclopropyl, fluorocyclopropyl,

R₂ is H or NH₂; R₃ is H or NH₂; R₄ is H or F; and R₅ is halo, methyl,trifluoromethyl, or methoxy.
 45. The compound of claim 17, wherein R₁,R₃, and R₅ are as provided in the following structures, wherein R₂ is Hor NH₂, R₄ is H or F and A is

and is represented by:


46. The compound of claim 45 wherein A is

wherein R_(c) and R_(f) are each independently H, (C₁-C₆)alkyl, orHO—(C₁-C₆)alkyl; R_(h), R_(i), and R_(j) are each independently H, OH,

 wherein

 indicates the point of attachment and Q is O or is absent,R_(ii)O(C₁-C₆)alkyl, R_(ii)O(C₁-C₆)haloalkyl, R_(ii)O(C₃-C₆)cycloalkyl,R_(ii)O(C₁-C₆)alkyl-O—, R_(ii)O(C₁-C₆)haloalkyl-O—,R_(ii)O(C₃-C₆)cycloalkyl-O—,

 wherein

 indicates the point of attachment, het is a 5- or 6-memberedheterocyclo or heteroaryl group that does not contain an NH, and x is aninteger of from 0 to 10;

 wherein

 indicates the point of attachment, het is as defined above, and y is aninteger of from 1 to 10, wherein R_(ii) is H, (C₁-C₆)alkyl,

 as defined above; provided that not all of R_(h) R_(i), and R_(j) areH.
 47. The compound of claim 46, wherein


48. (canceled)
 49. A pharmaceutical formulation comprising a compound offormula I, II, III, IV, V, VI, or VII admixed with a pharmaceuticallyacceptable diluent, carrier, or excipient.
 50. A method of treating abacterial infection in a mammal, comprising administering to a mammal inneed thereof an effective amount of a compound of formula I, II, III,IV, V, VI, or VII.